CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a continuation of, and claims priority to, U.S. patent application Ser. No. 15/520,317, filed Apr. 19, 2017, which is a 35 U.S.C. § 371 national phase application from, and claims priority to, International Application No. PCT/US2015/056232, filed Oct. 19, 2015 and published under PCT Article 21(2) in English, which claims priority to U.S. Provisional Patent Application No. 62/122,525, filed Oct. 23, 2014, all of which applications are incorporated herein by reference in their entireties.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant number 5-R01-HL097800 awarded by the National Heart, Lung, and Blood Institute and under grant number 12-DARPA-1068 awarded by the Defense Advanced Research Planning Agency. The government has certain rights in the invention.
BACKGROUND OF THE INVENTION Circadian rhythms are endogenous 24-hour oscillations in behavior and biological processes found in all lives. This internal clock allows an organism to adapt its physiology in anticipation of transitions between night and day. The circadian clock drives oscillations in a diverse set of biological processes, including sleep, locomotor activity, blood pressure, body temperature, and blood hormone levels (Levi, et al., 2007, Annu. Rev. Pharmacol. Toxicol., 47:593-628; Curtis et al, 2006, Ann. Med., 38:552-9). Disruption of normal circadian rhythms leads to clinically relevant disorders including neurodegeneration and metabolic disorders (Hastings, et al., 2013, Curr. Opin. Neurobiol., 23:880-7; Marcheva, et al., 2010, Nature, 466:627-631). In mammals, the molecular basis for these physiological rhythms arises from the interactions between two transcriptional/translational feedback loops (Lowrey, 2011, Adv. Genet., 74:175-230). Many members of the core clock regulate the expression of other transcripts. These clock-controlled genes mediate the molecular clock's effect on downstream rhythms in physiology.
There is a need in the art for a novel formulation of a therapeutic compound to improve its efficacy and safety according to the circadian rhythms. The present invention satisfies this need.
BRIEF SUMMARY OF THE INVENTION In one aspect, the present invention includes a formulation providing coordinated release of a therapeutic compound selected from Table 1, wherein release of the therapeutic compound from the formulation coincides with peak or trough expression of at least one target gene of the therapeutic compound. In certain embodiments, the at least one target gene is PPARα. In other embodiments, the target gene of the therapeutic compound is a niacin receptor, Niacr1. In yet other embodiments, the therapeutic compound is niacin. In yet other embodiments, the niacin is released zero to six hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In yet other embodiments, the therapeutic compound is dosed within one hour of a final meal before bedtime.
In another aspect, the formulation of the invention provides coordinated release of a first portion of the therapeutic compound and a second portion of the therapeutic compound such that release of the first portion of the therapeutic compound coincides with peak or trough expression of the at least one target gene and release of the second portion of the therapeutic compound occurs after peak or trough expression of the at least one target gene. In certain embodiments, release of the second portion of the therapeutic compound occurs prior to one half-life of the therapeutic compound following the first portion release. In other embodiments, release of the second portion of the therapeutic compound occurs after one half-life of the therapeutic compound following the first portion release. In yet other embodiments, release of the second portion of the therapeutic compound occurs after the release of substantially the entire first portion and prior to one half-life of the therapeutic compound following the release of the first portion. In yet other embodiments, release of the second portion of the therapeutic compound occurs prior to the release of substantially the entire first portion. In yet other embodiment, release of a second portion of the therapeutic compound contained in the formulation occurs at a time independent of an expression peak or trough of its target gene in a tissue type and wherein the release of the second portion avoids an undesirable side effect. In yet other embodiments, the formulation further provides release of at least a third portion of the therapeutic compound.
In yet another aspect, the therapeutic compound of the formulation inhibits at least two target genes and wherein the formulation provides coordinated release such that release of a first portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of a first target gene and release of a second portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of a second target gene. In certain embodiments, the formulation further provides release of at least a third portion of the therapeutic compound contained in the formulation such that release of the at least third portion coincides with peak or trough expression of at least a third target gene and wherein peak or trough expression of the at least third target gene is defined in Table 2. In other embodiments, the first target gene and the second target gene are each selected from Table 1. In yet other embodiments, peak or trough expression of the target gene in each tissue type is defined in Table 2. In yet other embodiments, each of the at least two target genes is selected from the group consisting of PPARα, PPARδ, and PPARγ. In yet other embodiments, the therapeutic compound is a fibrate having a half-life of less than six hours. In yet other embodiments, the fibrate is released two to four hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In yet other embodiments, the at least two target genes are expressed in at least two tissue types and wherein the formulation provides coordinated release of the therapeutic compound such that release of the first portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of the first target gene in the first tissue type and release of the second portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of the second target gene in the second tissue type.
In yet other aspect, the formulation provides coordinated release of the therapeutic compound such that release of a first portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of the at least one target gene in a first tissue type and release of a second portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of the at least one target gene in a second tissue type, and the at least one target gene is expressed in at least two tissue types. In certain embodiments, the first tissue type and the second tissue type are each selected from Table 1. In other embodiments, the first tissue type is liver and the second tissue type is kidney. In yet other embodiments, the therapeutic compound is Gemfibrozil or Bezafibrate. In yet other embodiments, the formulation further provides release of at least a third portion of the therapeutic compound contained in the formulation such that the release of the at least third portion coincides with peak or trough expression of the at least on target gene in an at least third tissue type and wherein peak or trough expression of the at least one target gene in the at least third tissue type is defined in Table 2. In yet other embodiments, the first target gene is PPARα and the first tissue type is liver. In yet other embodiments, the second target gene is PPARγ and the second tissue type is kidney. In yet other embodiments, the formulation provides release of at least a third portion of the therapeutic compound contained in the formulation such that the release of the at least third portion coincides with peak or trough expression of at least a third target gene and wherein peak or trough expression of the at least third target gene is defined in Table 2, optionally, wherein the at least a third target gene is expressed in a third tissue type.
In yet another aspect, the invention includes a formulation providing coordinated release of at least two therapeutic compounds selected from Table 1, wherein each therapeutic compound inhibits at least one different target gene wherein release of a first therapeutic compound from the formulation coincides with peak or trough expression of at least one target gene of the first therapeutic compound and wherein release of a second therapeutic compound from the formulation coincides with peak or trough expression of at least one target gene of the second therapeutic compound. In certain embodiments, release of the second therapeutic compound occurs at a specified time following release of the first therapeutic compound wherein the specified time correlates with a differential between peak or trough expression of at least one target gene of the first therapeutic compound and peak or trough expression of at least one target gene of the second therapeutic compound and wherein peak or trough expression of each target gene is defined in Table 2. In other embodiments, release of the second therapeutic compound occurs at a specified time following release of the first therapeutic compound wherein the specified time correlates with a differential in peak or trough expression of the target gene of the first therapeutic compound and the peak or trough expression of the target gene of the second therapeutic compound as defined in Table 2. In yet other embodiments, the target gene of the first therapeutic compound is Agtr1a and the target gene of the second therapeutic compound is Adrb2 or Adrb1. In yet other embodiments, the first therapeutic compound is an angiotensin receptor blocker (ARB) having a half-life of less than six hours and wherein the second therapeutic compound is a beta blocker having a half-life of less than three hours. In yet other embodiments, the ARB is released zero to two hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. and the beta blocker is released two to four hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In yet other embodiments, the ARB is Valsartan or Losartan and the beta blocker is Metoprolol or Timolol. In yet other embodiments, the target gene of the first therapeutic compound is Agtr1a and the target gene of the second therapeutic compound is Car4, Car2, Car12, or Car9. In yet other embodiments, the first therapeutic compound is an angiotensin receptor blocker (ARB) having a half-life of less than six hours and wherein the second therapeutic compound is a diuretic. In one embodiment, the ARB is released zero to two hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. and the diuretic is released six to eight hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In another embodiment, the ARB is Valsartan or Losartan and diuretic is Hydrochlorothiazide. In yet another embodiment, the target gene of the first therapeutic compound is Ace and the target gene of the second therapeutic compound is Adrb2 or Adrb1. In yet other embodiments, the first therapeutic compound is an acetylcholinesterase (ACE) inhibitor having a half-life of less than six hours and wherein the second therapeutic compound is a beta blocker having a half-life of less than three hours. In one embodiment, the ACE inhibitor is released zero to two hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. and the beta blocker is released two to four hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In another embodiment, the ACE inhibitor is Enalapril or Ramipril and the beta blocker is Metoprolol or Timolol. In yet other embodiments, the target gene of the first therapeutic compound is Ace and the target gene of the second therapeutic compound is Car4, Car2, Car12, or Car9. In one embodiment, wherein the first therapeutic compound is an acetylcholinesterase (ACE) inhibitor having a half-life of less than six hours and wherein the second therapeutic compound is a diuretic. In another embodiment, the ACE inhibitor is released zero to two hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. and the diuretic is released six to eight hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In yet another embodiment, the ACE inhibitor is Enalapril or Ramipril and diuretic is Hydrochlorothiazide. In yet other embodiments, the target gene of the first therapeutic compound is PPARα and the target gene of the second therapeutic compound is Hmgcr. In certain embodiments, the first therapeutic compound is a fibrate having a half-life of less than two hours and wherein the second therapeutic compound is a statin having a half-life of less than two hours. In one embodiment, the fibrate is released zero to two hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. and the statin is released four to six hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In another embodiment, the fibrate is principally metabolized by CYP3A4 and the statin is principally metabolized by CYP2C9. In yet another embodiment, the fibrate is Gemfibrozil and the statin is Fluvastatin. In other embodiments, the first therapeutic compound and the second therapeutic compound are dosed before bedtime and each exhibits normal pharmacokinetics once released from the formulation. In yet other embodiments, the formulation of the invention further provides release of at least a third therapeutic compound contained in the formulation such that release of the at least third therapeutic compound coincides with peak or trough expression of at least a third target gene and wherein peak or trough expression of the at least third target gene is defined in Table 2.
In yet another aspect, the formulation of the invention provides coordinated release of at least two different therapeutic compounds selected from Table 1, wherein the at least two therapeutic compounds have at least one common target gene, wherein release of a first therapeutic compound coincides with peak or trough expression of the common target gene and release of a second therapeutic compound coincides with peak or trough expression of the common target gene.
In yet another aspect, the invention includes a method for treating a disease in a subject in need thereof. The method comprises administering an effective amount of a formulation of the invention at a specified time, such that release of a therapeutic compound from the formulation coincides with peak or trough expression of at least one target gene of the therapeutic compound.
In yet another aspect, the invention includes a kit comprising a formulation of the invention and instructions for use. In certain embodiments, the instructions specify that the formulation is provided such that release of a first therapeutic compound or a first portion of the first therapeutic compound from the formulation coincides with peak or trough expression of at least one target gene of the first therapeutic compound.
In yet another aspect, the invention includes a method of developing an improved formulation for a therapeutic compound. The method comprises: identifying the circadian phase of gene expression of a target for the therapeutic compound; identifying a desired administration time; and calculating a difference between the circadian phase of the target gene expression and the desired administration time; and developing a delayed-release formulation corresponding to the calculated difference.
In yet another aspect, the invention includes a method of developing an improved formulation to reduce an undesired side effect of a therapeutic compound. The method comprises: identifying a circadian phase of gene expression of a target associated with the undesired side effect of the therapeutic compound; identifying a desired administration time to minimize the undesired side effect; calculating a difference between circadian phase of gene expression of the target and the desired administration time; and developing a delayed-release formulation corresponding to the calculated difference.
In yet another aspect, the invention includes a method of developing an improved formulation to reduce the metabolism of a therapeutic compound. The method comprises: identifying a circadian phase of expression of a metabolic enzyme involved in the metabolism of the therapeutic compound; identifying a desired administration time to minimize the metabolism of the therapeutic compound; calculating a difference between the circadian phase of expression of the metabolic enzyme and the desired administration time; and developing a delayed-release formulation corresponding to the calculated difference.
In yet another aspect, the invention includes a method of developing an improved formulation to increase the metabolism of a prodrug. The method comprises: identifying a circadian phase of expression of a metabolic enzyme involved in converting the prodrug to a drug; identifying a desired administration time to maximize the metabolism of the prodrug; calculating a difference between circadian phase of expression of the metabolic enzyme and the desired administration time; and developing a delayed-release formulation corresponding to the calculated difference.
In yet another aspect, the invention includes a method of developing an improved formulation to increase the transportation of a therapeutic compound to its desired target. The method comprises: identifying a circadian phase of expression of a transporter involved in the transportation of the therapeutic compound to its desired target; identifying a desired administration time to increase the transportation of the therapeutic compound to its desired target; calculating a difference between circadian phase of expression of the transporter and the desired administration time; and developing a delayed-release formulation corresponding to the calculated difference.
In yet another aspect, the invention includes a method of developing an improved formulation to decrease the transportation of a therapeutic compound to its undesired target. The method comprises: identifying a circadian phase of expression of a transporter involved in the transportation of the therapeutic compound to its undesired target; identifying a desired administration time to decrease the transportation of the therapeutic compound to its undesired target; calculating a difference between circadian phase of expression of the transporter and the desired administration time; and developing a delayed-release formulation corresponding to the calculated difference.
In certain embodiments, the therapeutic compound is selected from the group consisting of esomeprazole, valsartan, rituximab, fluticasone, lisdexamfetamine dimesylate, oseltamivir, methylphenidate, testosterone, lidocaine, quetiapine, sildenafil, niacin, insulin lispro, pemetrexed, ipratropium bromide/albuterol, albuterol sulfate, sitagliptin/metformin, metoprolol succinate, ezetimibe/simvastatin, rabeprazole, eszopiclone, omeprazole, dexmethylphenidate, enalapril, neostigmine, ephedrine, pyridostigmine, lisdexamfetamine, salmeterol, salbutamol, timolol, metoprolol, epinephrine, propranolol, hydralazine, acetazolamide, fludrocortisone, spironolactone, docetaxel, paclitaxel, nifedipine, pilocarpine, atropine, levamisole, carbidopa, flucytosine, levodopa, dopamine, naloxone, propofol, midazolam, ondansetron, ethionamide, vinblastine, hydrochlorothiazide, primaquine, gentamicin, dacarbazine, didanosine, cytarabine, cefazolin, metformin, tetracycline, misoprostol, sulfasalazine, ibuprofen, acetylsalicylic acid, riboflavin, verapamil, ketamine, ciprofloxacin, etoposide, propylthiouracil, mebendazole, fluorouracil, and allopurino. In one embodiment, the therapeutic compound is valsartan. In another embodiment, the desired administration time is between 5 pm and 9 pm.
In yet another aspect, the invention includes to a delayed-release formulation comprising a pharmaceutically effective amount of valsartan, wherein the valsartan is delayed to be released to gastrointestinal tract from the time when the valsartan is orally administered. In certain embodiments, the delay is about 6 hours. In other embodiments, the delayed-release formulation further comprises an erodible plug, an impermeable capsule body, and soluble cap.
In yet another aspect, the invention includes a method of maximizing the efficacy of a therapeutic compound in a subject. The method comprises identifying the circadian phase of the subject using a measuring device; identifying the target gene of the therapeutic compound; and administering the therapeutic compound to the subject at the circadian phase when the target gene for the therapeutic compound is maximally or minimally expressed; wherein the measuring device is installed with a suitable application that identifies or tracks the circadian phases of the subject. In one embodiment, the therapeutic compound is streptozocin.
BRIEF DESCRIPTION OF THE DRAWINGS For the purpose of illustrating the invention, there are depicted in the drawings certain embodiments of the invention. However, the invention is not limited to the precise arrangements and instrumentalities of the embodiments depicted in the drawings.
FIG. 1 illustrates the breakdown of circadian genes and non-coding RNAs. Panel A illustrates the number of protein-coding genes in each organ that exhibit circadian expression. Blue marks indicate the number of genes with at least 1 spliceform detected by RNA-seq. Orange marks indicate the number of genes with at least 2 spliceforms detected by RNA-seq. Blue numbers to the right of each bar list the percentage of protein coding genes with rhythmic expression in each tissue. Panel B is a graph illustrating the distribution of the number of organs in which a protein-coding gene oscillated according to the circadian cycle. Panel C is a graph illustrating average total number of circadian genes detected as a function of the number of organs sampled. Panel D is a graph illustrating the percentages of each transcript class that did vs. did-not oscillate in at least one organ.
FIG. 2 illustrates parameters of circadian gene expression across organs. Panel A is a graph illustrating the relationship between organ, oscillation amplitude and oscillation phase of circadian gene expression. Upper-left quadrant illustrates histograms of amplitudes within each organ (number of circadian genes expressed within each amplitude bin is shown on the horizontal axis, grouped by organ). Upper-right quadrant illustrates histograms of amplitudes of expression within each phase, across all organs. Lower-right quadrant illustrates histograms of phases of expression within each organ, with summary radial diagrams (number of circadian genes within each phase bin is shown on the vertical axis, grouped by organ). Lower-left quadrant illustrates Venn diagrams of the identities of the genes whose expression oscillated within a given pair of organs. Panel B is schematic ontogenic tree constructed using the average phase differences between each organ pair's shared circadian gene expression as the distance metric. Shared gene expression corresponds to the overlapping regions from Venn diagrams in panel A.
FIG. 3 illustrates pathways of gene expression across biological space and time. Panel A illustrates a superimposed circadian graph of the deltex gene Dtx4 expression in all organs tested. Panel B illustrates an example of pathway components' timing of gene expression reflecting function: expression profiles from the heart, for Vegfa and its two receptors Kdr and Flt1. Black arrows highlight times at which Flt1 and Kdr are anti-phased. Panel C illustrates an example of systemic pathway of gene expression orchestration segregating in time and space: expression profile of Igf1 in the liver, as compared to its downstream target Pik3 in several organs. Panel D illustrates an example of widespread pathway gene expression component synchronization within the same space (organ): expression profiles from the kidney for multiple signaling receptors that activate the PIK3-AKT-MTOR pathway.
FIG. 4 illustrates the overlap of circadian disease gene expression and drug targets. Panel A is a schematic diagram illustrating overlap between expression of circadian genes, expression of known disease-associated genes, and expression of drug targets. Panel B illustrates an example of a common drug having an oscillatory target gene expression: expression profiles for the aspirin target Ptgs1 from heart, lung, and kidney. Traces of expression from these organs of the mir22 host gene, predicted to target Ptgs1, are also shown. Panel C illustrates the number of PubMed references disclosing circadian vs. non-circadian genes.
FIG. 5 illustrates oscillating transcripts from expression of genes across different organs. Panel A is a graph illustrating the effect of 5% false-discovery rate for detection. Panel B is a graph illustrating the average total number of oscillating genes expressed and detected as a function of the number of organs sampled. Panel C is a set of radial diagrams illustrating the phase distribution of oscillating gene expression in each organ.
FIG. 6 illustrates conserved circadian non-coding RNAs (ncRNAs). Panel A is a schematic diagram illustrating method overview for identifying conserved ncRNAs. Panel B is a diagram illustrating functional types of circadian conserved ncRNAs. Types were defined by GENCODE and Ensembl biotypes, assigned by using Ensembl and manual annotation.
FIG. 7 illustrates representative examples of conserved circadian ncRNAs and anti-sense transcripts. Panel A is a RNA-seq coverage plot for Galt (red) and its antisense transcript (blue). The gene model for Galt is displayed above the coverage plots. Panel B comprises two graphs illustrating expression profiles for Galt (red; data from microarrays) and the antisense transcripts (blue; data from RNA-seq). Gray regions indicate subjective night. Panel C is a RNA-seq coverage plot for Snhg12. The gene model is displayed below the coverage plot. Note the locations of the mature small nucleolar RNA (snoRNA) sequences located in the introns of Snhg12. Panel D comprises two graphs illustrating RNA-seq expression profiles for Snhg12 in brown adipose and hypothalamus. Panel E is a RNA-seq coverage plot for Arnt1 (red) and its antisense transcript (blue), from white adipose tissue. The gene model for Arnt1 is displayed above the coverage plots. Panel F comprises two graphs illustrating expression profiles for Arnt1 (red; data from microarrays) and the antisense transcripts (blue; data from RNA-seq), from white adipose tissue and liver. Panel G is a RNA-seq coverage plot for Per2 (red) and its antisense transcript (blue), from white adipose tissue. The gene model for Per2 is displayed above the coverage plots. Panel H comprises four graphs illustrating expression profiles for Per2 (red) and the antisense transcript (blue) from liver, adrenal gland, lung, and kidney.
FIG. 8 illustrates genomic characteristics common to rhythmically-expressed genes. Panel A comprises a plot and a gene map illustrating genomic clustering of each organ's oscillatory gene expression. The test-statistic used was the sum of the squared number of oscillatory genes expressed within a sliding nine-gene window (intergenic distance disregarded). Significance values were derived using null distributions determined by randomly shuffling gene positions 1-million times for each organ-chromosome pair. Panel B is a graph illustrating the total length of circadian vs. non-circadian genes. Panel C is a graph illustrating length of circadian vs. non-circadian genes across 5′UTRs. Panel D is a graph illustrating length of circadian vs. non-circadian genes across CDS length. Panel E is a graph illustrating length of circadian vs. non-circadian genes across 3′UTRs. Panel F is a graph illustrating spliceforms counts of circadian vs. non-circadian gene expression for detected spliceforms. Panel G is a graph illustrating spliceforms counts of circadian vs. non-circadian gene expression for unique sets of spliceforms expressed across organs. Panel H is a graph illustrating spliceforms counts of circadian vs. non-circadian gene expression for unique, dominant spliceforms expressed across organs. Panel I is a graph illustrating number of genes having the given maximum phase difference in expression between any two organs. Vegfa is shown as an example.
FIG. 9 illustrating expression of core circadian oscillator genes across organs. Panel A is a scheme illustrating expression of each gene in all organs superimposed. Panel B is a heatmap representation of expression of the circadian genes described in Panel A.
FIG. 10 is a scheme illustrating the method of discovering oscillation influence on pathways. Nodes represent Reactome pathways, with size corresponding to total number of genes in a pathway and color corresponding to percent of genes with rhythmic expression at the organism level. Edges convey pathway hierarchy. Heatmap depicts significance of pathways' oscillatory fractions by Fisher's exact test at the organ level.
FIG. 11 illustrates that Mir22 expression reduced endogenous PTGS1 in NIH3T3 cells. Panel A is a graph illustrating the representative Western blot analysis of lysates from NIH3T3 cells transfected with mirNeg, mir-22-3p, or mir-22-5p. Panel B is a graph illustrating densitometric quantification of PTGS1 protein expression from Western blots, normalized to GAPDH protein expression. Values are mean intensities relative to the mirNeg condition, ±SD. Panel C is a graph illustrating the quantification of Ptgs1 mRNA by qPCR from the same samples assayed in FIG. 11, Panel B.
FIG. 12 is a set of graphs illustrating circadian expression of core clock genes and drug targets in human lung. Data from human lung samples were downloaded from the NCBI GEO database (GSE23546). Using CYCLOPS and a set of ˜1000 homologs of clock-regulated genes in the mouse, 1349 human lung samples were re-ordered in periodic space. Each blue dot represents data from a single sample, while the red line indicates the best fit to the cosine trend. Plotted are expression levels of 33 core clock gene and drug target transcripts. If a gene had multiple clock-regulated transcripts, they were plotted. For example, CLOCK and CRY1, core clock genes, and DBP and TEF, output regulators, are expressed with high amplitude circadian rhythms as evaluated by cosinor regression. As seen in animal models, CRY1 (RORE regulated) and DBP/TEF (E-box) regulated are opposite phase. Several drug targets were also found to be clock regulated in human lung samples. For example, DDC, PDE4A, PDE4B, PDE5A, PPARA, and XDH were all found to be clock-regulated.
FIG. 13 is a set of graphs illustrating circadian expression of core clock genes and drug targets in human liver. Data from human lung samples were downloaded from the NCBI GEO database (GSE9588). Using CYCLOPS, 427 human liver samples were re-ordered in periodic space. Each blue dot represents data from a single sample, while the red line indicates the best fit to the cosine trend. Plotted are 20 core clock genes and drug target transcripts. If a gene had multiple clock-regulated transcripts, they were plotted. For example, CLOCK and CRY1, core clock genes, and DBP and TEF, output regulators, are expressed with high amplitude circadian rhythms as evaluated by cosinor regression. As seen in animal models, CRY1 (RORE regulated) and DBP (E-box) regulated are opposite phase. Several drug targets were also found to be clock regulated in human liver samples. For example, AGTR1, DDC, PDE4A, PDE4B, PDE5A, PPARA, and XDH were all found to be clock-regulated.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the unexpected discovery of patterns of circadian gene expression within various organs and tissues of a human. The invention further relates to a method of developing an improved formulation of a therapeutic substance to improve its efficacy and reduce its side effects according to the expression of these circadian genes.
Definitions As used herein, each of the following terms has the meaning associated with it in this section.
Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in animal pharmacology, pharmaceutical science, separation science and organic chemistry are those well-known and commonly employed in the art.
As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.
As used herein, the term “about” is understood by persons of ordinary skill in the art and varies to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
As used herein, the terms “adverse effect” and “side effect” are used interchangeably. Both refer to an undesired harmful effect resulting from a medication.
As used herein, the phrase “before bedtime” means up to 6 hours prior to bedtime, e.g., 1 hour, 2 hours, three hours, four hours, five hours, and 6 hours prior. Before bedtime also means at or about bedtime. In certain embodiments, it includes at the time of a final meal prior to bedtime. Bedtime is relative to a subject. For example, a subject who sleeps during the day will have a bedtime in the morning and a standard subject who sleeps at night bill have a bedtime in the evening.
The terms “carrier” or “carrier system” means one or more compatible substances that are suitable for delivering, containing, or “carrying” therapeutic compound ingredient(s) for administration to a patient or subject.
As used herein, the term “chronotherapy” refers to the use of circadian time in determining optimal formulation and dosage of therapeutic compounds to be administered.
As used herein, the term “circadian gene” refers to any gene identified whose expression cycles with a 24-hour period.
As used herein, the term “circadian hour” is defined as the unit of time corresponding to 1/24 of the duration of a circadian cycle. By convention, the onset of locomotor activity of diurnal organisms defines circadian time zero (CT 0). Thus, the onset of activity of nocturnal organisms defines circadian time twelve (CT 12).
As used herein, the terms “circadian phase” and “circadian cycle” are used interchangeably. Both refer to the phase of a circadian rhythm where its peak and trough occur within 24 hours.
As used herein, the term “circadian time” refers to a standard of time based on the free-running period of a rhythm (oscillation).
As used herein, the term “coordinated release” refers to release of at least one therapeutic compound such that the release of the therapeutic compound coincides with peak or trough expression of one or more target genes of the therapeutic compound.
As used herein, the term “drug target” refers to genes whose expression products are bound by or are otherwise functionally affected by a given drug.
As used herein, the term “delayed-release” refers to a medication that does not immediately disintegrate and release the active ingredient into the body of a mammal when administered thereto.
As used herein, the term “delayed-release formulation” refers to a formulation delaying the active ingredient's release to the body of a mammal.
As used herein, the term “enteric coating” relates to a polymer barrier applied on an oral medication. In one instance, the enteric coating works by presenting a barrier wrapping around the active ingredient of an oral medication. Such barrier is stable at the highly acidic PH found in the stomach, but breaks down rapidly at a less acidic or basic environment.
The term “extended-release” is used herein with reference to a drug formulation that releases the therapeutic compound slowly into the bloodstream over time. The advantage of extended-release formulations is to take at less frequent intervals than immediate-release formulations of the same drug.
As used herein, the term “half-life” refers to the duration of time required for the concentration or amount of drug in the body to be reduced by one-half. Generally, the half-life of a drug relates to the amount of the drug in plasma.
The term “immediate-release” is used herein with reference to a drug formulation that does not contain a dissolution rate controlling material. There is substantially no delay in the release of the active ingredient following administration of an immediate-release formulation.
As used herein, the term “inhibit” as it relates to a gene refers to restraining or preventing the expression of the gene, including production of the corresponding RNA or protein.
As used herein, the terms “peak phase” and “peak expression” are used interchangeably. Both refer to the time when the circadian genes or protein expressed thereby are most active.
As used herein, the term “pharmaceutically-acceptable excipients” refers to any physiologically inert, pharmacological inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the active ingredient selected for use. Pharmaceutically-acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, lubricants, solvents, co-solvents, surfactants, preservatives, sweetener agents, flavoring agents, buffer systems, pharmaceutical-grade dyes or pigments, and viscosity agents. Flavoring agents among those useful herein include those described in Remington's Pharmaceutical Sciences, 18th Edition Mack Publishing Company, 1990, pp. 1288-1300, incorporated by reference herein. Dyes or pigments among those useful herein include those described in Handbook of Pharmaceutical Excipients pp. 81-90, 1986 by the American Pharmaceutical Association & the Pharmaceutical Society of Great Britain, incorporated by reference herein.
As used herein, “pharmaceutically acceptable salts” refer to derivatives of the therapeutic compound wherein the parent compound is modified by making an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, and arginine.
As used herein, the term “pharmaceutical composition” means an oral dosage form comprised of a safe and effective amount of an active ingredient and a pharmaceutically-acceptable excipient.
As used herein, “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of a disease or disorder.
The phrase “reducing the risk of”, as used herein, means to lower the likelihood or probability of a disease or disorder from occurring in a patient or subject, especially when the patient or subject is predisposed to such or at risk of contracting a disease or disorder.
One of ordinary skill in the art will appreciate that there is some overlap in the definitions of “treating”, “preventing”, and “reducing the risk of”.
As used herein, the term “prodrug” refers to a medication that is administered in an inactive or less than fully active form, and is then converted to its active form through a normal metabolic process, such as hydrolysis of an ester form of the drug.
As used herein, the terms “safe and effective amount”, “effective amount”, and “pharmaceutically effective amount” are used interchangeably. All refers to an amount of a compound or composition high enough to significantly positively modify the symptoms and/or condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The safe and effective amount of active ingredient for use in the method of the invention herein will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient being employed, the particular pharmaceutically-acceptable excipient utilized, and like factors within the knowledge and expertise of the attending physician.
As used herein, the phrase “pharmaceutically acceptable” refers to those therapeutic compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
As used herein, the phrase “release of a therapeutic compound” means that the therapeutic compound enters plasma and reaches at safe and effective amount.
As used herein, the phrase “regulated release” includes immediate-release, extended-release, delayed release, or combination thereof.
As used herein, the terms “synchronize” and “coincide” are used interchangeably. Both refers to an action matching the time when a therapeutic compound reaches safe and effective amount in plasma with the peak or trough of circadian genes or proteins.
A “subject” or “patient,” as used therein, may be a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the subject is human.
As used herein, the term “tablet” is intended to encompass compressed formulations of all shapes and sizes whether coated or uncoated. As used herein, the term “capsule” or “caplet” is intended to encompass a powdered, pelleted, or beaded formulations enclosed in a shell, e.g., a gelatin shell such as a soft gelatin or hard gelatin capsule.
As used herein, the terms “therapeutic substance,” “drug,” “therapeutic compound,” and “active ingredient” are used interchangeably. All refer to a substance having or exhibiting healing power, curing or mitigating the symptoms of a disease.
As used herein, the phrase “time-release” includes extended-release, delayed release, or combination thereof.
As used herein, the term “transporter” refers to a transport protein that serves the function of moving other material within an organism.
The term “treating”, as used herein, means to cure an already present disease or disorder. Treating can also include inhibiting, i.e., arresting the development of a disease or disorder, and relieving or ameliorating, i.e., causing regression of the disease or disorder.
As used herein, the term “trough” or “trough expression” refers to the time when the target genes or proteins expressed thereby are least active.
It is to be understood that, wherever values and ranges are provided herein, the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, all values and ranges encompassed by these values and ranges are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range and, when appropriate, partial integers of the numerical values within ranges. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, and so on, as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
DESCRIPTION The present invention relates to methods for developing formulations for treating one or more diseases, conditions, or disorders associated with genes that are expressed with circadian rhythms (i.e., genes that oscillate with circadian rhythm). Such formulations have regulated release of at least one therapeutic compound such that the compound's release coincides with peak or trough expression of one or more of the compound's target genes and in at least one tissue type.
The design of appropriate formulation(s) is within the routine level of skill in the art. Before formulations are designed, it is first necessary to identify the disorders and as well as the therapeutic compounds capable of treating the disorder. Then, target gene(s) for the therapeutic compounds are ascertained. Examples of suitable disorders, therapeutic compounds, target gene(s) for the various therapeutic compounds, and the half-lives of exemplary therapeutic compounds are listed in Table 1, infra.
Next, circadian oscillations in transcript expression (including peak and trough expressions) for the target genes in specific tissue types are determined, for example, by using the methods described herein. Data regarding circadian oscillations, including coding and non-coding genes, are available via the World Wide Web (www) bioinf dot itmat dot upenn dot edu/circa, a subset of which is summarized in Table 2, infra.
Using the information provided in Tables 1 and 2, as well as methods well known in the art for making appropriate immediate release and/or time-releases formulations, suitable formulation(s) can be devised that will be useful in treating disease(s), condition(s), or disorder(s) associated with genes that are expressed with circadian rhythms.
For example, formulations can be prepared for situations where a given therapeutic compound has one target gene in one tissue; where a given therapeutic compound has more than one target gene in one tissue; where therapeutic compound(s) have a target gene that is differentially expressed in more than one tissue type; and/or where therapeutic compound(s) have two (or more) target genes that are differentially expressed in more than one tissue type. Formulations can also be designed to include more than one therapeutic compound, wherein the more than one therapeutic compound may have two (or more) target genes that are differently expressed, in time and/or in tissue types. In addition, formulations can also be designed including more than two (e.g., three, four, five, or more) therapeutic compounds.
In other embodiments, formulations can also be designed such that one therapeutic compound is released coincidental with peak or trough expression of its target gene and a second therapeutic compound is released at times that may be independent of its target gene's peak or trough expression. It is often preferable to temporally segregate a therapeutic effect from unwanted side effects. For example, certain statins can cause rhabdomyolysis, which is breakdown of muscle fibers that leads to the release of muscle fiber contents (myoglobin) into the bloodstream. Thus, it is ideal if a statin's therapeutic effect of lipid lowering in the liver is temporally segregated from a side effect of muscle fiber breakdown.
The present invention also includes coordinated release of a therapeutic compound selected from Table 1, wherein release of the therapeutic compound from the formulation coincides with peak or trough expression of at least one target gene of the therapeutic compound. For example, the at least one target gene is selected from Table 1. In these formulations, the therapeutic compound is released at a defined time (in hours) after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. Those skilled in the art will recognize that, while the exact time for release of the therapeutic compound from the formulation is application specific, the defined time will never be higher than 12 hours.
In one specific example, the at least one target gene is PPARα, and the therapeutic compound may be a fibrate having a half-life of less than six hours. In such formulations, the fibrate is released two to four hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. Suitable fibrates for use in such formulations include, but are not limited to, Gemfibrozil or Bezafibrate. Ideally, the formulation is taken by a patient before bedtime (e.g., at bedtime or two to six hours before bedtime) and exhibits normal pharmacokinetics once released from the formulation.
In another specific example, the target gene is Niar1, a niacin receptor, and the therapeutic compound may be niacin (i.e., less than about 500 mg niacin per dose). In such formulations, the niacin is released zero to six hours (e.g., zero to two hours; two to four hours; or four to six hours) after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. The therapeutic compound can be dosed before bedtime (e.g., at bedtime or two to six hours before bedtime) and exhibits normal pharmacokinetics once released from the formulation. The therapeutic compound may also be dosed within one hour of a final meal before bedtime. The niacin can be immediate-released once release from a formulation has begun.
Also included are formulations providing coordinated release of a therapeutic compound selected from Table 1, wherein release of the therapeutic compound from the formulation coincides with peak or trough expression of at least one target gene of the therapeutic compound. The formulation comprises two portions of the therapeutic compound: a first portion and a second portion, and provides coordinated release of the two portions of the therapeutic compound such that release of the first portion of the therapeutic compound coincides with peak or trough expression of the at least one target gene and release of the second portion of the therapeutic compound occurs after peak or trough expression of the at least one target gene.
In such formulations, the first portion of the therapeutic compound is immediate-released or is time-released.
In various embodiments, the release of the second portion of the therapeutic compound occurs prior to one half-life of the therapeutic compound following the first portion release; occurs after one half-life of the therapeutic compound following the first portion release; occurs after the release of substantially the entire first portion and prior to one half-life of the therapeutic compound following the release of the first portion; or occurs prior to the release of substantially the entire first portion.
In some formulations, release of a second portion of the therapeutic compound contained in the formulation occurs at a time independent of an expression of its target gene in a tissue type and avoids undesirable side effect(s).
Also included are formulations providing coordinated release of a therapeutic compound selected from Table 1, wherein the therapeutic compound inhibits at least two target genes and wherein the formulation provides coordinated release such that release of a first portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of a first target gene and release of a second portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of a second target gene. For example, the first target gene and the second target gene are each selected from Table 1, and the peak or trough expression of the first target gene and peak or trough expression of the second target gene are defined in Table 2.
The first portion of the therapeutic compound can be released 0 to 2 hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C.
The second portion of the therapeutic compound can be released 2-6 hours following the first portion is released, which correlates with a differential in peak or trough expression of the first and second target genes as defined in Table 2.
In such formulations, the release of a second portion of the therapeutic compound contained in the formulation occurs at a time independent of a differential in peak or trough expression of a first target gene and a second target gene as defined in Table 2 and avoids undesirable side effect(s).
The first portion of the therapeutic compound can be immediate-released or time-released.
These formulations further comprise at least a third portion of the therapeutic compound. The release of the at least third portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of at least a third target gene and wherein peak or trough expression of the at least third target gene is defined in Table 2.
In one specific example, the at least two target genes is selected from the group consisting of PPARα, PPARδ, and PPARγ. In such formulations, the therapeutic compound is a fibrate (e.g., Bezafibrate) having a half-life of less than six hours. For example, the fibrate is released two to four hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. Ideally, in these formulations, the therapeutic compound is dosed before the patient's bedtime and exhibits normal pharmacokinetics once released from the formulation.
Also included are formulations providing coordinated release of a therapeutic compound selected from Table 1, wherein release of the therapeutic compound from the formulation coincides with peak or trough expression of at least one target gene of the therapeutic compound, wherein the target gene is expressed in at least two tissue types and wherein the formulation provides coordinated release of the therapeutic compound such that release of a first portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of the target gene in a first tissue type and release of a second portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of the target gene in a second tissue type. In such formulations, the target gene is selected from Table 1 and/or the peak or trough expression of the target gene in each tissue type is defined in Table 2. The first tissue type and the second tissue type are each selected from Table 1.
In these formulations, the first portion of the therapeutic compound is released 0-2 hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. The second portion of the therapeutic compound is released 2-6 hours following the release of the first portion, which correlates with a differential in peak or trough expression of the target gene between the first and second tissue types as defined in Table 2.
In such formulations, the release of a second portion of the therapeutic compound contained in the formulation occurs at a time independent of a differential in peak or trough expression of a first target gene and a second target gene as defined in Table 2 and avoids undesirable side effect(s).
The first portion of the therapeutic compound can be immediate-released or time-released.
In one specific example, the target gene is PPARα, the first tissue type is liver and the second tissue type is kidney. In such formulations, the therapeutic compound is Gemfibrozil or Bezafibrate. The therapeutic compound can be dosed before bedtime.
Such formulations can also provide release of at least a third portion of the therapeutic compound contained in the formulation such that the release of the at least third portion coincides with peak or trough expression of the target gene in an at least third tissue type and wherein peak or trough expression of the target gene in the at least third tissue type is defined in Table 2.
Also included are formulations providing coordinated release of a therapeutic compound selected from Table 1, wherein the therapeutic compound inhibits at least two target genes, wherein the formulation provides coordinated release such that release of a first portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of a first target gene and release of a second portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of a second target gene, wherein the at least two target genes are expressed in at least two tissue types and wherein the formulation provides coordinated release of the therapeutic compound such that release of the first portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of the first target gene in the first tissue type and release of the second portion of the therapeutic compound contained in the formulation coincides with peak or trough expression of the second target gene in the second tissue type. In such formulations, the first target gene and the second target gene are each selected from Table 1 and/or peak or trough expression of the first target gene and peak or trough expression of the second target gene are defined in Table 2.
The first portion of the therapeutic compound can be immediate-released or time-released.
In these formulations, the first portion of the therapeutic compound can be released 0-2 hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. The second portion of the therapeutic compound can be released 2-6 hours following the release of the first portion, which correlates with a differential in peak or trough expression of the first and second target genes as defined in Table 2.
In one specific example, the first target gene is PPARα and the first tissue type is liver. In this example, the second target gene is PPARγ and the second tissue type is kidney. The therapeutic compound is Bezafibrate. In this formulation, the therapeutic compound is dosed before bedtime.
Such formulations may additionally provide release of at least a third portion of the therapeutic compound contained in the formulation such that the release of the at least third portion coincides with peak or trough expression of at least a third target gene and wherein peak or trough expression of the at least third target gene is defined in Table 2, optionally, wherein the at least a third target gene is expressed in a third tissue type.
Also included is a formulation comprising at least two therapeutic compounds selected from Table 1, wherein each therapeutic compound inhibits at least one different target gene wherein release of a first therapeutic compound from the formulation coincides with peak or trough expression of at least one target gene of the first therapeutic compound and wherein release of a second therapeutic compound from the formulation coincides with peak or trough expression of at least one target gene of the second therapeutic compound. Release of the second therapeutic compound occurs a specified time following release of the first therapeutic compound wherein the specified time correlates with a differential between peak or trough expression of at least one target gene of the first therapeutic compound and peak or trough expression of at least one target gene of the second therapeutic compound and wherein peak or trough expression of each target gene is defined in Table 2. Release of the second therapeutic compound can also occur at a specified time following release of the first therapeutic compound wherein the specified time correlates with a differential between peak or trough expression of the at least one target gene of the first therapeutic compound in a first tissue type and peak or trough expression of the at least one target gene of the second therapeutic compound in a second tissue type and wherein peak or trough expression of each target gene in each tissue type is defined in Table 2.
The first target gene and the second target gene can each be selected from Table 1.
For example, release of the second therapeutic compound occurs at a specified time following release of the first therapeutic compound wherein the specified time correlates with a differential in peak or trough expression of the target gene of the first therapeutic compound and the peak or trough expression of the target gene of the second therapeutic compound as defined in Table 2.
The first therapeutic compound may be immediate-released or time-released.
In these formulations, the first therapeutic compound is released 0-2 hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. The second therapeutic compound can be released 2-4 hours following release of the first therapeutic compound, which correlates with a differential in peak or trough expression of the target gene of the first therapeutic compound and the target gene of the second therapeutic compound as defined in Table 2.
In one specific example, the target gene of the first therapeutic compound is Niacr1, or a niacin receptor and the target gene of the second therapeutic compound is Hmgcr. For example, when the first therapeutic compound is niacin (e.g., less than 500 mg per dose) and the second therapeutic compound is a statin (e.g., Cerivastatin, Fluvastatin, or Simvastatin) having a half-life of less than three hours, niacin is released two to four after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. and the statin is released four to six after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In such formulations, the first therapeutic compound and the second therapeutic compound are dosed before bedtime (e.g., within 2 hours of bedtime or within one hour of a final meal before bedtime) and each exhibits normal pharmacokinetics once released from the formulation.
In one specific example of such a formulation, the target gene of the first therapeutic compound is Agtr1a and the target gene of the second therapeutic compound is Adrb2 or Adrb1. For example, when the first therapeutic compound is an angiotensin receptor blocker (ARB) having a half-life of less than six hours (e.g., Valsartan or Losartan) and wherein the second therapeutic compound is a beta blocker having a half-life of less than three hours (e.g., Metoprolol or Timolol), the ARB can be released zero to two hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. and the beta blocker can be released two to four hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In these formulations, the first therapeutic compound and the second therapeutic compound are dosed before bedtime and each exhibits normal pharmacokinetics once released from the formulation.
In another specific example of such a formulation, the target gene of the first therapeutic compound is Agtr1a and the target gene of the second therapeutic compound is Car4, Car2, Car12, or Car9. For example, when the first therapeutic compound is an angiotensin receptor blocker (ARB) having a half-life of less than six hours (e.g., Valsartan or Losartan) and the second therapeutic compound is a diuretic (e.g., Hydrochlorothiazide), the ARB can be released zero to two hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. and the diuretic can be released six to eight hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In these formulations, the first therapeutic compound and the second therapeutic compound each exhibit normal pharmacokinetics once released from the formulation.
In a further specific example of such a formulation, the target gene of the first therapeutic compound is Ace and the target gene of the second therapeutic compound is Adrb2 or Adrb1. For example, when the first therapeutic compound is an acetylcholinesterase (ACE) inhibitor having a half-life of less than six hours (e.g., Enalapril or Reamipril) and the second therapeutic compound is a beta blocker having a half-life of less than three hours (e.g., Metoprolol or Timolol), the ACE inhibitor can be released zero to two hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. and the beta blocker can be released two to four hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In these formulations, the first therapeutic compound and the second therapeutic compound are dosed before bedtime and each exhibits normal pharmacokinetics once released from the formulation.
In yet another specific example of such a formulation, the target gene of the first therapeutic compound is Ace and the target gene of the second therapeutic compound is Car4, Car2, Car12, or Car9. For example, when the first therapeutic compound is an acetylcholinesterase (ACE) inhibitor having a half-life of less than six hours (e.g., Enalapril or Reamipril) and the second therapeutic compound is a diuretic (e.g., Hydrochlorothiazide), the ARB can be released zero to two hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. and the diuretic can be released six to eight hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In these formulations, the first therapeutic compound and the second therapeutic compound each exhibit normal pharmacokinetics once released from the formulation.
In another embodiment, target gene of the first therapeutic compound is PPARα and the target gene of the second therapeutic compound is Hmgcr. For example, when the first therapeutic compound is a fibrate having a half-life of less than two hours and the second therapeutic compound is a statin having a half-life of less than two hours, the fibrate can be
released zero to two hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. and the statin can released four to six hours after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. In these formulations, the fibrate is principally metabolized by CYP3A4 (e.g., Gemfibrozil) and the statin is principally metabolized by CYP2C9 (e.g., Fluvastatin). In these formulations, the first therapeutic compound and the second therapeutic compound can be dosed before bedtime and are each exhibits normal pharmacokinetics once released from the formulation.
Any of these formulations can further provide release of at least a third therapeutic compound contained in the formulation such that release of the at least third therapeutic compound coincides with peak or trough expression of at least a third target gene and wherein peak or trough expression of the at least third target gene is defined in Table 2.
Also included are formulations providing coordinated release of at least two different therapeutic compounds selected from Table 1, wherein the at least two therapeutic compounds may independently inhibit more than two target genes, but have at least one common target gene, wherein release of a first therapeutic compound coincides with peak or trough expression of the common target gene at one time and release of a second therapeutic compound coincides with peak or trough expression of the common target gene at a different time. In such formulations, the first therapeutic compound has a half-life that differs from the half-life of the second therapeutic compound and wherein the half-lives of the first therapeutic compound and the second therapeutic compound are identified in Table 1. The first therapeutic compound has a half-life shorter than the half-life of the second therapeutic compound. Alternatively, the first therapeutic compound has a half-life longer than the half-life of the second therapeutic compound. In these formulations, the first therapeutic compound is immediate-release or time-released. Likewise, the second therapeutic compound is immediate-release or time-released.
In various embodiments, the first therapeutic compound is released before peak or trough expression of the common target gene and the second therapeutic compound is released after peak or trough expression of the common target gene or the first and second therapeutic compounds are both released before peak or trough expression of the common target gene.
In further embodiments, the release of the second therapeutic compound occurs a specified time following release of the first therapeutic compound and wherein the specified time correlates with a differential in half-lives between the first and second therapeutic compounds as defined in Table 2.
The common target gene of the first and second therapeutic compounds is selected from Table 1.
In these formulations, the first therapeutic compound is released at a defined time (in hours) following after contact with a solution having a pH of between 1 and 5 and a temperature of between 35 and 42° C. Determination of the defined time is within the routine level of skill in the art. Likewise, the second therapeutic compound is released at a defined time (in hours) following release of the first therapeutic compound, which correlates with a differential in half-lives between the first and second compounds as defined in Table 2. Determination of this defined time is within the routine level of skill in the art.
The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990) and Remington: The Science and Practice of Pharmacy, 22nd Edition, Baltimore, Md.: Lippincott Williams & Wilkins, 2012, both of which are herein incorporated by reference.
Additionally, any of the therapeutic compounds of the present invention, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dehydrates. Non-limiting examples of solvates include ethanol solvates and acetone solvates.
The therapeutic compounds of the present invention can also be prepared as esters, for example pharmaceutically acceptable esters. For example a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, an ethyl, and another ester. Also, an alcohol group in a compound can be converted to its corresponding ester, e.g., an acetate, a propionate, and another ester.
The therapeutic compounds of the present invention can also be prepared as prodrugs, for example pharmaceutically acceptable prodrugs. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the therapeutic compounds of the present invention can be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed therapeutic compounds, methods of delivering the same and compositions containing the same. “Prodrugs” are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include therapeutic compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
The formulations disclosed herein may optionally contain an immediate release portion. An immediate release portion of the formulation may to release more than 50%, (e.g., 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or essentially all) of the therapeutic compound(s) in the at least one immediate release portion(s) within about one hour. In certain embodiments, more than 50% and up to essentially all the therapeutic compound(s) in the at least one immediate release portion(s) may be released in less than about 45 min. In other embodiments, more than 50% and up to essentially all the therapeutic compound(s) in the at least one immediate release portion(s) may be released in less than about 30 min. In yet other embodiments, more than 50% and up to essentially all the therapeutic compound(s) in the at least one immediate release portion(s) may be released in less than about 20 min. In yet other embodiments, more than 50% and up to essentially all the therapeutic compound(s) in the at least one immediate release portion(s) may be released in less than about 15 min. In yet other embodiments, more than 50% and up to essentially all the therapeutic compound(s) in the at least one immediate release portion(s) may be released in less than about 10 min. In yet other embodiments, more than 50% and up to essentially all the therapeutic compound(s) in the at least one immediate release portion(s) may be released in less than about 5 min.
Formulation: The formulation of the present invention includes one or more of the following essential and optional components. The formulation of the present invention also includes therapeutic compound(s).
Suitable carrier components are described in e.g., Eds. R. C. Rowe, et al., Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press (2006); Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990); and Remington: The Science and Practice of Pharmacy, 22nd Edition, Baltimore, Md.: Lippincott Williams & Wilkins, 2012. Even though a functional category can be provided for many of these carrier components, such a functional category is not intended to limit the function or scope of the component, as one of ordinary skill in the art will recognize that a component can belong to more than one functional category and that the level of a specific component and the presence of other components can affect the functional properties of a component.
a. Emulsifier
The formulations of the present invention may include at least one emulsifier. Useful emulsifiers include polyglycolized glycerides (also known as polyglycolysed glycerides). These materials are generally surface active and depending on their exact composition have a range of melting points and hydrophilic/lipophilic balance ranges (HLBs). These materials are often further combined with a polyhydric alcohol, such as glycerol. The polyglycolized glycerides are mixtures of glycerides of fatty acids and of esters of polyoxyethylene with fatty acids. In these mixtures, the fatty acids are generally saturated or unsaturated C8-C22, for example C8-C12 or C16-C20. The glycerides are generally monoglycerides, diglycerides, or triglycerides or mixtures thereof in any proportions. Polyglycolysed glycerides are marketed e.g., by Gattefosse under the trade names Labrafil, Labrosol, and Gelucire. The Gelucire polyglycolized glycerides are often designated with the melting point and HLB. For example, Gelucire 53/10 refers to a material having a melting point of 53° C. and an HLB of 10. Gelucire materials useful herein include Gelucire 44/14 and Gelucire 50/13. Other emulsifiers useful herein include vitamin E TPGS, ploxamers, and lecithin. Vitamin E TPGS is also known as d-α-tocopheryl polyethylene glycol 1000 succinate. Ploxamers are known by the trade name Pluronics, and are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)).
The emulsifier can constitute from about 0.1% to about 99.9% of the formulation of the present invention. In embodiments, the emulsifier can constitute from about 1% to about 20%, from about 1% to about 15%, and from about 1% to about 10% of the formulation of the present invention.
b. Polymeric Dissolution Aid
The formulations of the present invention may include at least one polymeric dissolution aid. Such polymeric dissolution aids include polymers of 1-ethenyl-2-pyrrolidinone; polyamine N-oxide polymers; copolymers of N-vinylpyrrolidone and N-vinylimidazole; polyvinyloxazolidones and polyvinylimidazoles or mixtures thereof. Particularly useful are polymers of 1-ethenyl-2-pyrrolidinone, especially the homopolymer. Generally this homopolymer has a molecular weight range of about 2500 to 3,000,000. This homopolymer is known as polyvinylpyrollidone, PVP, or povidone and in other instances can function as a dissolution aid, disintegrant, suspending agent, or binder.
The polymeric dissolution aid can constitute from about 0.1% to about 99.9% of the formulations of the present invention. In certain embodiments, the polymeric dissolution aid can constitute from about 1% to about 10%, from about 1% to about 5%, and from about 1% to about 2.5% of the formulations of the present invention.
c. Binder
The formulations of the present invention can include at least one binder or binding agent. Examples of binders are cellulose; microcrystalline cellulose; low viscosity water soluble cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, and sodium carboxy-methyl cellulose; alginic acid derivatives; polyvinylpyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; sugars (including sucrose, glucose, dextrose and lactose); waxes; gums (e.g., guar gum, arabic gum, acacia gum, and xanthan gum); and tragacanth. A preferred binder is HPMC. Preferably the binding agent constitutes from about 1 to about 10%. Preferably, the binder constitutes from about 1 to about 4% by weight of the formulation.
d. pH Modifier The formulations of the present invention can further include at least one pH modifier. Examples of pH modifiers are generally acidic or basic materials that can be used to modify or adjust the pH of the formulation or its environment. Non-limiting examples of pH modifiers useful herein include aspartic acid, citric acid, ethanesulfonic acid, fumaric acid, lactic acid, methanesulfonic acid, tartaric acid, and mixtures thereof.
e. Filler
The formulations of the present invention can further include at least one filler. Examples of fillers are microcrystalline cellulose; glucose; lactose; dextrose; mannitol; sorbitol; sucrose; starches; fumed silica; salts such as sodium carbonate and calcium carbonate; and polyols such as propylene glycol. Preferably, fillers are present in an amount of from 0% to about 50% by weight of the formulations, either alone or in combination. More preferably they are present from about 5% to about 20% of the weight of the formulation.
f. Dispersing or wetting agent
The formulations of the present invention can further include at least one dispersing or wetting agent. Examples of dispersing or wetting agents are polymers such as polyethylene-polypropylene, and surfactants such as sodium lauryl sulfate. Preferably the dispersing or wetting agent is present in an amount of from 0% to about 50% by weight, either alone or in combination. More preferably they are present from about 5% to about 20% of the weight of the formulation.
g. Disintegrant
The formulations of the present invention can further include at least one disintegrant. Examples of disintegrants are modified starches or modified cellulose polymers, e.g., sodium starch glycolate. Other disintegrants include agar; alginic acid and the sodium salt thereof; effervescent mixtures (e.g., the combination of an acid such as tartaric acid or citric acid and a basic salt such as sodium or potassium bicarbonate, which upon contact with an aqueous environment react to produce carbon dioxide bubbles which help to break up or disintegrate the composition); croscarmelose; crospovidone; sodium carboxymethyl starch; sodium starch glycolate; clays; and ion exchange resins. Preferably the disintegrant is present in an amount of from 0% to about 50% by weight of the formulation, either alone or in combination. More preferably the disintegrant is present from about 5% to about 20% by weight of the formulation.
h. Lubricant
The formulations of the present invention can further include at least one lubricant. Generally, the lubricant is selected from a long chain fatty acid or a salt of a long chain fatty acid. Suitable lubricants are exemplified by solid lubricants including silica; talc; stearic acid and its magnesium salts and calcium salts; calcium sulfate; and liquid lubricants such as polyethylene glycol; and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. Preferably the lubricant is present in an amount of from 0% to about 50% by weight of the formulation, either alone or in combination. More preferably it is present from about 5% to about 20% of the weight of the formulation.
i. Additional Components
The formulations of the present invention can further include one or more additional components selected from a wide variety of excipients known in the pharmaceutical formulation art. According to the desired properties of the tablet or capsule, any number of ingredients can be selected, alone or in combination, based upon their known uses in preparing the formulations of the present invention. Such ingredients include, but are not limited to, water, nonaqueous solvents (e.g., ethanol), coatings, capsule shells, colorants, waxes, gelatin, flavorings, preservatives (e.g., methyl paraben, sodium benzoate, and potassium benzoate), antioxidants (e.g., ascorbic acid, butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E and vitamin E esters such as tocopherol acetate), flavor enhancers, sweeteners (e.g., aspartame and saccharin), compression aids, and surfactants. Exemplary coating agents include, but are not limited to: sodium carboxymethyl cellulose, cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl methyl cellulose phthalate, methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, gellan gum, maltodextrin, methacrylates, microcrystalline cellulose and carrageenan or mixtures thereof.
Extended-Release Formulation: In certain embodiments, the therapeutic compound described herein may have little side effect in treating the intended disease, and the desired administration time is not convenient, an extended-release formulation is desirable. In other embodiments, an extended-release formulation may be used in combination with a delayed-release formulation or an immediate-release formulation to exploit the circadian gene expression.
The formulations disclosed herein may include at least one extended-release portion containing the therapeutic compound(s) and an extended-release component. Suitable extended-release components include, for example, polymers, resins, hydrocolloids, hydrogels, and the like.
Suitable polymers for inclusion in an extended-release portion of the formulation may be linear, branched, dendrimeric, or star polymers, and include synthetic hydrophilic polymers as well as semi-synthetic and naturally occurring hydrophilic polymers. The polymers may be homopolymers or copolymers, such as random copolymers, block copolymers, and graft copolymers. Suitable hydrophilic polymers include, but are not limited to: polyalkylene oxides, particularly poly(ethylene oxide), polyethylene glycol and poly(ethylene oxide)-poly(propylene oxide) copolymers; cellulosic polymers, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, microcrystalline cellulose, and polysaccharides and their derivatives; acrylic acid and methacrylic acid polymers, copolymers and esters thereof, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, and copolymers thereof, with each other or with additional acrylate species such as aminoethyl acrylate; maleic anhydride copolymers; polymaleic acid; poly(acrylamides) such as polyacrylamide per se, poly(methacrylamide), poly(dimethylacrylamide), and poly(N-isopropyl-acrylamide); polyalkylene oxides; poly(olefinic alcohol)s such as poly(vinyl alcohol); poly(N-vinyl lactams) such as poly(vinyl pyrrolidone), poly(N-vinyl caprolactam), and copolymers thereof; polyols such as glycerol, polyglycerol (particularly highly branched polyglycerol), propylene glycol and trimethylene glycol substituted with one or more polyalkylene oxides, e.g., mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di-polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol and polyoxyethylated glucose; polyoxazolines, including poly(methyloxazoline) and poly(ethyloxazoline); polyvinylamines; polyvinylacetates, including polyvinylacetate per se as well as ethylene-vinyl acetate copolymers, polyvinyl acetate phthalate, and the like, polyimines, such as polyethyleneimine; starch and starch-based polymers; polyurethane hydrogels; chitosan; polysaccharide gums; xanthan gum; zein; shellac, ammoniated shellac, shellac-acetyl alcohol, and shellac n-butyl stearate. The polymers may be used individually or in combination. Certain combinations will often provide a more extended-release of certain therapeutic compounds than their components when used individually. Suitable combinations include cellulose-based polymers combined with gums, such as hydroxyethyl cellulose or hydroxypropyl cellulose combined with xanthan gum, and poly(ethylene oxide) combined with xanthan gum.
In certain embodiments, the extended-release polymer(s) may be a cellulosic polymer, such as an alkyl substituted cellulose derivative as detailed above. In terms of their viscosities, one class of exemplary alkyl substituted celluloses includes those whose viscosity is within the range of about 100 to about 110,000 centipoise as a 2% aqueous solution at 20 □C. Another class includes those whose viscosity is within the range of about 1,000 to about 4,000 centipoise as a 1% aqueous solution at 20 □C.
In certain embodiments, the extended-release polymer(s) may be a polyalkylene oxide. In other embodiments, the polyalkylene oxide may be poly(ethylene oxide). In yet other embodiments, the poly(ethylene oxide) may have an approximate molecular weight between 500,000 Daltons (Da) to about 10,000,000 Da or about 900,000 Da to about 7,000,000 Da. In yet a further embodiment, the poly(ethylene oxide) may have a molecular weight of approximately 600,000 Da, 700,000 Da, 800,000 Da, 900,000 Da, 1,000,000 Da, 2,000,000 Da, 3,000,000 Da, 4,000,000 Da, 5,000,000 Da, 6,000,000 Da, 7,000,000 Da, 8,000,000 Da 9,000,000 Da, or 10,000,000 Da. The poly(ethylene oxide) may be any desirable grade of POLYOX™ or any combination thereof. By way of example and without limitation, the POLYOX™ grade may be WSR N-10, WSR N-80, WSR N-750, WSR 205, WSR 1105, WSR N-12K, WSR N-60K, WSR-301, WSR Coagulant, WSR-303, WSR-308, WSR N-3000, UCARFLOC Polymer 300, UCARFLOC Polymer 302, UCARFLOC Polymer 304, and UCARFLOC Polymer 309. In still another embodiment, the poly(ethylene oxide) may have an average number of repeating ethylene oxide units (—CH2CH2O—) of about 2,000 to about 160,000. In yet another embodiment, the poly(ethylene oxide) may have an average number of repeating ethylene oxide units of about 2,275, about 4,500, about 6,800, about 9,100, about 14,000, about 20,000, about 23,000, about 45,000, about 90,000, about 114,000, or about 159,000.
Often extended-release formulations utilize an enteric coating. Enteric coatings prevent release of medication before it reaches the small intestine. Enteric coatings may contain polymers of polysaccharides, such as maltodextrin, xanthan, scleroglucan dextran, starch, alginates, pullulan, hyaloronic acid, chitin, chitosan and the like; other natural polymers, such as proteins (albumin, gelatin etc.), poly-L-lysine; sodium poly(acrylic acid); poly(hydroxyalkylmethacrylates) (for example poly(hydroxyethylmethacrylate)); carboxypolymethylene (for example Carbopol™); carbomer; polyvinylpyrrolidone; gums, such as guar gum, gum arabic, gum karaya, gum ghatti, locust bean gum, tamarind gum, gellan gum, gum tragacanth, agar, pectin, gluten and the like; poly(vinyl alcohol); ethylene vinyl alcohol; polyethylene glycol (PEG); and cellulose ethers, such as hydroxymethylcellulose (HMC), hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose (MC), ethylcellulose (EC), carboxyethylcellulose (CEC), ethylhydroxyethylcellulose (EHEC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxypropylmethyl-cellulose (HPMC), hydroxypropylethylcellulose (HPEC) and sodium carboxymethylcellulose (Na CMC); as well as copolymers and/or (simple) mixtures of any of the above polymers. Certain of the above-mentioned polymers may further be crosslinked by way of standard techniques.
The choice of polymer will be determined by the nature of the therapeutic compound that is employed in the formulation as well as the desired rate of release. In particular, it will be appreciated by the skilled person, for example in the case of HPMC, that a higher molecular weight will, in general, provide a slower rate of release of therapeutic compound from the formulation. Furthermore, in the case of HPMC, different degrees of substitution of methoxy groups and hydroxypropoxyl groups will give rise to changes in the rate of release of therapeutic compound from the formulation. In this respect, and as stated above, it may be desirable to provide formulation of the disclosure in the form of coatings in which the polymer carrier is provided by way of a blend of two or more polymers of, for example, different molecular weights in order to produce a particular required or desired release profile. The coating can be any of a number of materials conventionally used such for extending drug release such as ethyl cellulose, the Eudragit™ polymers (manufactured by Degussa Rohm Pharma Polymers of Germany), Aquacoat™ (by FMC Biopolymer) and Surelease™ (by Colocon Inc.)
A therapeutic compound is said to be “encapsulated” or “embedded” within a polymer when it is not covalently bound to the polymer but is surrounded by material making up the polymer so that it cannot escape therefrom under physiological conditions unless the permeability of the polymer is enhanced.
This invention provides methods for controlled delivery of an amine-, alcohol-, or thiol-containing therapeutic compound to a patient by providing a therapeutic compound-delivery molecule. Here, the therapeutic compound's amine nitrogen, alcohol oxygen, or thiol sulfur is covalently attached via to a carbon atom of a drug-delivery molecule. The drug-delivery molecule also includes a masked release-enhancing moiety. When the therapeutic compound-delivery molecule is exposed to selected conditions under which an unmasking reaction occurs a release-enhancing moiety facilitates breaking of the covalent bond attaching the therapeutic compound from the drug-delivery molecule, and the therapeutic compound is released. The release-enhancing moiety may be a nucleophilic moiety, an electron-donating moiety or an electron-withdrawing moiety, as more fully described below. The selected conditions may be any conditions inside a patient's body, such as acidic conditions within a patient's stomach or more basic conditions within a patient's intestine.
The covalent bond between the therapeutic compound and the drug-delivery molecule is preferably broken by an intramolecular reaction, such as between the release enhancing moiety and the carbon atom to which the therapeutic compound is covalently attached. To prevent the therapeutic compound from being active before the desired time and place of release inside a patient's body, another moiety, preferably a polymeric moiety, is covalently attached to the therapeutic compound-delivery molecule.
The rate of release of the therapeutic compound from the therapeutic compound-delivery molecule can be controlled by a number of means including controlling the unmasking reaction, or controlling the breaking of the covalent-bond attaching the therapeutic compound to the drug-delivery molecule. The unmasking reaction can be controlled by selecting a more easily hydrolyzable masking group for the therapeutic compound-delivery molecule when a faster rate is desired and a less easily hydrolyzable masking group when a slower reaction is desired. The release reaction can be used to control the release rate of the therapeutic compound by providing a more powerful release-enhancing moiety when a faster rate is desired, and a less powerful release-enhancing moiety when a slower rate is desired. When the release-enhancing moiety is an electron donor or an electron-withdrawing moiety, a more or less powerful electron donor or electron-withdrawing moiety can be used to control the release rate. When the release rate depends on a nucleophilic release-enhancing moiety, a more nucleophilic moiety can be used for a faster rate, and a less nucleophilic moiety can be used for a slower rate.
Delayed-Release Formulation Delayed-release formulation of a therapeutic compound can be developed in a number of ways, either using a device, or a capsule comprising a delayed release formulation, or by providing an enteric coating. Non-limiting examples of delayed-release formulations are disclosed herein. It should be noted that delayed release formulations are not limited solely to oral administration of therapeutic compounds, but rather the invention contemplates the use of delayed release formulations useful for delivery of a therapeutic compound via any route available for that compound, such as oral administration, topical administration, transdermal administration, rectal administration, inhalation, and injection.
Non-limiting examples of delayed release formulations for oral delivery are now described. Mahajan (Mahajan et al., 2010, Ars Pharm, 50:215-223), incorporated herein by reference in its entirety, discloses a timed delayed capsule device for chronotherapy. Such capsule device is prepared by sealing the drug tablet and the expulsion excipient inside the insoluble hard gelation capsule body with erodible tablet plug and a soluble cap. Once orally administered, the capsule cap dissolves, and the tablet plug slowly erodes away until a certain time to expose the active ingredient. Accordingly, there is lag time between when the capsule is administered and when the active ingredient is released into the body. The lag time (delayed-release) can be adjusted according to the desired administration time by adding or removing the amount of tablet plug.
PCT/US1992/009385, incorporated herein by reference in its entirety, discloses a delayed-released formulation comprising a core with an enteric coating material. The core includes a pharmaceutical composition. The enteric coating material is a pharmaceutically acceptable excipient that allows the therapeutic compound in the core to be released into the body after certain amount of time.
Alternatively, a delayed-release formulation can be developed by using a barrier coating that delays the release of the active ingredient. The barrier coating may consist of a variety of different materials, depending on the objective. In addition, a formulation may comprise a plurality of barrier coatings to facilitate release in a temporal manner. The barrier coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or a coating based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose. Furthermore, the formulation may additionally include a time delay material such as, for example, glyceryl monostearate or glyceryl distearate.
A delayed-release formulation may further comprise a pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient can be a disintegrator, a binder, a filler, a lubricant, or combination thereof used in formulating pharmaceutical products.
In a delayed-release formulation, the delay may be up to 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, or longer.
A delayed-release formulation may comprise 1-80% of a given therapeutic compound administered in a single unit dose. In certain embodiments, the delayed-release formulation comprises about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 of the therapeutic compound to be delivered by the formulation.
In certain embodiments, a delayed-release formulation of a therapeutic compound may be administered concurrently with an immediate-release formulation of the same therapeutic compound. Alternatively, a delayed-release formulation of a therapeutic compound may be administered concurrently with an immediate-release formulation of a different therapeutic compound.
In certain embodiment, the delayed-release formulation mixes with the immediate-release formulation to form a pharmaceutical composition before administration.
Valsartan is a once daily drug for treatment of high blood pressure, congestive heart failure, or post-myocardial infarction. Its action mechanism is to block the action of angiotensin. That leads to dilation of blood vessels and hence reduces blood pressure. The drug target of valsartan is circadian gene Agtr1a expression. Its peak phase is about 6 hours after sleep and trough is about 8 hours after awakening. The concentration of Valsartan in plasma reaches the maximum 2-4 hours after administration. For a patient whose desired administration time is same as bedtime 10 pm, the delayed-release formulation of valsartan delays the release of valsartan 2-4 hours.
In one embodiment, the delayed-release formulation comprises a pharmaceutically effective amount of valsartan, wherein the release of valsartan to gastrointestinal tract is delayed about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, or longer, and any and all whole or partial integers there between. The delayed-release formulation of valsartan further comprises an erodible plug, an impermeable capsule body, and soluble cap. These components of the delayed-release formulation of valsartan are configured in the same way as that described in Mahajan (Mahajan et al., 2010, Ars Pharm, 50:215-223).
In another embodiment, the delayed-release formulation of valsartan can be added or mixed with the immediate-release formulation of valsartan to form a pharmaceutical composition of valsartan, then the pharmaceutical composition of valsartan is orally administered. Alternatively, the delayed-release formulation of valsartan is separated from the immediate-release formulation of valsartan, but both are concurrently administered.
Methods The present invention also includes methods for treating a disease, disorder, or condition by administering an effective amount of any of the formulations described herein at a specified time such that release of a therapeutic compound from the formulation coincides with peak or trough expression of at least one target gene for the therapeutic compound. For example, the disease, disorder, or condition may be cancer, diabetes mellitus type 2, Alzheimer's disease, schizophrenia, Down's syndrome, obesity, coronary artery disease, and/or any other disease, disorder, or condition associated with circadian genes.
Also included is a method of developing an improved formulation for a therapeutic compound to improve its efficacy. The method comprises: identifying the circadian phase of a target gene for the therapeutic compound; identifying a desired administration time; and calculating a difference between the circadian phase of the target gene expression and the desired administration time. The method further comprises developing a delayed-release formulation based on the calculated difference to synchronize the therapeutic compound's safe and effective amount in plasma with the target's peak phase of gene expression.
In one aspect, the invention includes a method of developing an improved formulation to reduce an undesired side effect of a therapeutic compound. The method comprises: identifying a circadian phase of a target gene associated with the undesired side effect of the therapeutic compound; identifying a desired administration time to minimize the undesired side effect; and calculating a difference between circadian phase of target gene expression and the desired administration time. The method further comprises developing a delayed-release formulation based on the calculated difference to synchronize the therapeutic compound's safe and effective amount in plasma with the target gene's trough expression.
Another aspect of the present invention includes a method of developing an improved formulation to reduce the metabolism of a therapeutic compound. The method comprises: identifying the circadian phase of expression of a metabolic enzyme involved in the metabolism of the therapeutic compound; identifying a desired administration time to minimize the metabolism of the therapeutic compound; and calculating a difference between the circadian phase of expression of the metabolic enzyme and the desired administration time. The method further comprises developing a delayed-release formulation based on the calculated difference to synchronize the therapeutic compound's safe and effective amount in plasma with the metabolic enzyme's trough expression. This means by which the parameters herein are assessed and used are similar to those already described herein for determining the timing of expression and therefore administration of therapeutic compounds in general.
Another aspect of the present invention includes a method of developing an improved formulation to increase the metabolism of a prodrug. The method comprises: identifying the circadian phase of expression of a metabolic enzyme involved in the metabolism of the prodrug; identifying a desired administration time to maximize the metabolism of the prodrug; and calculating a difference between the circadian phase of expression of a metabolic enzyme that converts the prodrug to a drug and the desired administration time. The method further comprises developing a delayed-release formulation based on the calculated difference to synchronize the prodrug's safe and effective amount in plasma with the metabolic enzyme's peak phase of expression.
Another aspect of the present invention includes a method of developing an improved formulation to increase the transportation of a therapeutic compound to its desired target. The method comprises: identifying the circadian phase of expression of a transporter involved in the transportation of the therapeutic compound to its desired target; identifying a desired administration time to increase the transportation of the therapeutic compound to its desired target; and calculating a difference between the circadian phase of expression of the transporter and the desired administration time. The method further comprises developing a delayed-release formulation based on the calculated difference to synchronize the therapeutic compound's safe and effective amount in plasma with the transporter's peak phase of expression.
Another aspect of the present invention includes a method of developing an improved formulation to decrease the transportation of a therapeutic compound to its undesired target. The method comprises: identifying the circadian phase of expression of a transporter involved in the transportation of the therapeutic compound to its undesired target; identifying a desired administration time to decrease the transportation of the therapeutic compound to its undesired target; and calculating a difference between the circadian phase of expression of the transporter and the desired administration time. The method further comprises developing a delayed-release formulation based on the calculated difference to synchronize the therapeutic compound's safe and effective amount in plasma with the transporter's trough of expression.
In certain embodiments, a target associated with a therapeutic compound, also called drug target, can be a DNA, a RNA, a DNA expression, a RNA expression, a protein, a metabolic protein, a transporter, or combination thereof. For example, the target for esomeprazole, a drug for the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome, is a protein encoded by Atp4a gene. Non-limiting examples of other drug targets are provided herein in Table 1 and Table 2.
In one embodiment, a non-limiting example of a therapeutic compound used in the methods of the invention is selected from Table 1.
In another embodiment, a non-limiting example of a therapeutic compound used herein in the methods of the invention is selected from the group consisting of esomeprazole, valsartan, rituximab, fluticasone, lisdexamfetamine dimesylate, oseltamivir, methylphenidate, testosterone, lidocaine, quetiapine, sildenafil, niacin, insulin lispro, pemetrexed, ipratropium bromide/albuterol, albuterol sulfate, sitagliptin/metformin, metoprolol succinate, ezetimibe/simvastatin, rabeprazole, eszopiclone, omeprazole, dexmethylphenidate, enalapril, neostigmine, ephedrine, pyridostigmine, lisdexamfetamine, salmeterol, salbutamol, timolol, metoprolol, epinephrine, propranolol, hydralazine, acetazolamide, fludrocortisone, spironolactone, docetaxel, paclitaxel, nifedipine, pilocarpine, atropine, levamisole, carbidopa, flucytosine, levodopa, dopamine, naloxone, propofol, midazolam, ondansetron, ethionamide, vinblastine, hydrochlorothiazide, primaquine, gentamicin, dacarbazine, didanosine, cytarabine, cefazolin, metformin, tetracycline, misoprostol, sulfasalazine, ibuprofen, acetylsalicylic acid, riboflavin, verapamil, ketamine, ciprofloxacin, etoposide, propylthiouracil, mebendazole, fluorouracil, and allopurinol.
In yet another embodiment, the therapeutic compound is valsartan.
The desired administration time varies according to expression of the therapeutic target, dosage of the therapeutic compound, the half-life of the therapeutic compound, and the disease associated with the therapeutic target. In certain embodiments, the desired administration time is between 6 am and 9 am or between 9 am and 12 am or 5 pm and 12 am. In one embodiment, the desired administration time is between 5 pm and 9 pm. In another embodiment, the desired administration time is between 6 pm and 8 pm. In yet another embodiment, the desired administration time is between 6 pm and 7 pm.
The half-life of a therapeutic compound is critical in determining the desired administration time. The half-life of the therapeutic compound can be found in the Orange Book of US Food and Drug Administration or can be measured by one skilled in the art. The half-lives of common therapeutic compounds, for example, are listed in Table 1.
Also included are methods for designing a formulation for treating a disorder in a subject in need thereof. Such methods may involve one or more of the steps of (1) identifying one or more therapeutic compounds that treat the disorder; (2) ascertaining at least one target gene for the one or more therapeutic compounds; (3) determining the peak or trough expression for the at least one target gene in one or more target tissues; and/or (4) devising or designing one or more formulation(s) such that release of the one or more therapeutic compounds coincides with the peak or trough expression for the at least one target gene in one or more target tissues. In some embodiments, the methods additionally include the step of determining the half-life of the one or more therapeutic compounds.
In yet another aspect of the invention, there is included a method of maximizing the efficacy of a therapeutic compound in a subject by administering the therapeutic compound at a time dictated by the circadian phase of the subject, where the circadian phase of the subject is monitored by a device. The method comprises identifying the circadian phase of a subject using any measuring device available in the art that can monitor a subject's circadian phase. The therapeutic compound is then administered to the subject at the precise circadian phase wherein the target gene is maximally or minimally expressed. In certain embodiments without limitation, the device is a smart phone, a smart watch, an activity tracker, or any other known or as yet unknown device installed with a suitable application that identifies or tracks the circadian phases of a subject's circadian phase. Measurement of a subject's circadian phase informs the timing of therapeutic compound delivery to the subject. The method is useful for timing the delivery of any therapeutic compound to the subject, whether formulated or unformulated, but may be particularly useful in situations where the therapeutic compound is administered by injection. In one non-limiting example, timing the delivery of the therapeutic compound streptozocin to a subject is included. Streptozocin is used for treating metastatic pancreatic islet cell carcinoma and is normally administered in a hospital setting by intravenous infusion. Streptozocin is a genotoxic agent and toxic to both the kidney and liver. In the method of the present invention, a subject's circadian cycle is monitored such that the circadian phase for minimal expression of the target gene for streptozocin, Slc2a2, is identified and the infusion of streptozocin is then timed to coincide with minimal expression of Slc2a2 in the subject. As many tumors have lost their circadian clock, timing streptozocin administration to the minimal phase of Slc2a2 expression will improve the therapeutic window and allow subjects to remain on streptozocin longer. The method of the invention should not be construed to be limited to any particular therapeutic compound or any particular measuring device, but should instead include any and all therapeutic compounds to be administered to a subject where the circadian cycle of the subject is measured so that the therapeutic compound is administered at a time when appropriate expression of the target gene is evident.
The circadian phase of the subject may also be measured physiologically, for example, by measuring melatonin levels in the subject.
Kits
The invention also includes kits for performing any of these methods including the formulation and instructions for use which define when the formulation is provided to a subject in need. Likewise, kits include any of the formulations described herein along with instructions for use which define when the formulation is provided to a subject in need. For example, in such kits, the instructions may specify that the formulation is provided such that release of a first therapeutic compound or a first portion of the first therapeutic compound from the formulation coincides with peak or trough expression of at least one target gene of the first therapeutic compound.
The pharmaceutical formulations of the present invention can be included in a container, pack, or dispenser together with instructions for use and/or administration.
In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the invention vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. In preferred aspects, dosages can range from about 1 mg/kg per day to about 1000 mg/kg per day. In an aspect, the dose will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about 1 g/day, in single, divided, or continuous doses (which dose may be adjusted for the patient's weight in kg, body surface area in m2, and age in years). An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.
The total amount of each therapeutic compound present in a formulation can and will vary. Depending on the therapeutic compound, the total amount of a therapeutic compound in a formulation can be between 1 μg to about 2000 mg per dose. In certain embodiments, the amount of therapeutic compound may be between about 1 μg to about 1 mg, e.g., 1 μg, 2, μg, 3 μg, 4 μg, 5 μg, 5.5 μg, 6.0 μg, 6.5 μg, 7.0 μg, 7.5 μg, 8.0 μg, 8.5 μg, 9.0 μg, 9.5 μg, 10 μg, 10.5 μg, 11 μg, 11.5 μg, 12 μg, 12.5 μg, 13 μg, 13.5 μg, 14 μg, 14.5 μg, 15 μg, 15.5 μg, 16 μg, 16.5 μg, 17 μg, 17.5 μg, 18 μg, 18.5 μg, 19 μg, 19.5 μg, 20 μg, 22.5 μg, 25 μg, 27.5 μg, 30 μg, 32.5 μg, 35 μg, 37.5 μg, 40 μg, 45 μg, 50 μg, 60 μg, 70 μg, 80 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, 160 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 900, μg, and 1 mg. In other embodiments, the amount of therapeutic compound may be between about 1 mg to about 2000 mg, e.g., 1 mg, 2, mg, 3 mg, 4 mg, 5 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 900, mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, and 2000 mg.
Throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the methods or processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
Described herein are RNA sequencing and DNA microarrays that characterize circadian oscillations in transcript expression across twelve mouse organs. It was found that the RNA abundance of 43% of mouse protein-coding genes cycle in at least one organ. Based on these results, it is estimated that over half of the mouse protein-coding genome is rhythmic somewhere in the body.
In most organs, expression of many oscillating genes peaked during transcriptional “rush hours” preceding dawn and dusk. A majority of these transcriptional rhythms were found to be organ-specific. The major exception to this finding is the set of core clock genes, which oscillated in phase across all twelve organs (see FIG. 1). Those skilled in the art will recognize that external cues such as restricted feeding or jet-lag could phase-shift these peripheral oscillators with respect to one another. However, these findings agree with the notion that peripheral clocks are largely synchronized in a healthy organism.
Additionally, oscillations in the expression of more than one thousand known and novel non-coding RNAs (ncRNAs) were also observed. ncRNAs conserved between human and mouse oscillated in the same proportion as protein coding genes, and this data supports ncRNAs believed role in mediating clock function. While some of these rhythmic ncRNAs have recognized functions, like snoRNA and miRNA host genes, little is known about the majority. The oscillations of these ncRNAs may prove advantageous for functional studies, e.g., linking a cycling miRNA to its predicted target genes by comparing their cycles.
Table 1 includes a list of top selling therapeutic compounds, their half-lives, the disease/disorder treated by the therapeutic compound, the target gene or gene product targeted by the therapeutic compound, and the organs in which the target gene is expressed.
TABLE 1
List of Top Selling Therapeutic Compounds
Therapeutic ½ Life
Compound in hours Disorder(s) Target gene(s) Tissue Type
Abiraterone 5 Cancer, Prostate Cancer Cyp17a1 Liver
Acarbose 2 Diabetes Drugs, Diabetes Gaa Aorta, Kidney
Mellitus, Diarrhea,
Flatulence, Type 2 Diabetes
Acebutolol 3 Hypertension, Liver Adrb2, Adrb1 Adr, Kidney, Lung, Mus
Acepromazine 3 Hypotension, Priapism, Adra1a, Htr2a, Adra1b BFAT, BS, Heart,
Schizophrenia Kidney, Liver, Lung,
Mus, WFAT
Acetaminophen 1 Ptgs2, Ptgs1 Aorta, Heart, Kidney,
Lung
Acetazolamide 3 Cystinuria, Glaucoma, Car14, Car4, Aqp1, Adr, Aorta, BFAT, BS,
Hypertension, Idiopathic Car3, Car2 Cere, Heart, Kidney,
Intracranial Hypertension, Liver, Lung, Mus
Intracranial Hypertension,
Seizure, Sleep
Acetohexamide 1.3 Diabetes Mellitus Kcnj1 Kidney
Acetylcysteine 5.6 Autism, Cough, CP, Cystic Grin3a, Slc7a11, Adr, BS, Cere, Hypo,
Fibrosis, Inhalation, Liver, Grin2b, Gss, Acy1, Kidney, Liver, Lung
Pulmonary Fibrosis Chuk, Ikbkb, Grin2d
Aclidinium 2.4 COPD Chrm3, Chrm2, Chrm4 Adr, BS, Heart, Kidney,
Liver, Lung
Adinazolam 3 Liver Gabra3, Gabrg3, Adr, Aorta, BFAT, BS,
Gabrb1, Gabra2, Cere, Heart, Hypo,
Gabrr2, Gabra5, Kidney, Lung, Mus,
Gabrb2, Gabrb3, WFAT
Gabrp, Gabrr1
Agomelatine 2 CP, Depressive Disorder, Htr2c, Mtnr1a Cere, Liver
Sleep
Aldesleukin 0.216 Il2rg, Il2rb, Il2ra Adr, Heart, Liver, Lung,
Mus
Alfentanil 1.5 Breathing, Depression, Oprm1 BS
Liver, Pain
Alglucosidase alfa 2.3 M6pr Kidney, Liver, WFAT
Allopurinol 1 Gout, Hyperuricemia Xdh Adr, Aorta, BFAT, BS,
Cere, Heart, Kidney,
Liver, Lung, Mus
Almotriptan 3 Headache, Liver, Migraine, Htr1b, Htr1d Adr, BS, Lung
Migraine Headache
Alprenolol 2 Adrb2, Adrb1 Adr, Kidney, Lung, Mus
Alprostadil 5 Ptger2, Ptger1 Aorta, Heart
Amifostine 0.133 Cancer, Chemotherapy, Enpp1 Adr, Liver
Radiotherapy
Aminocaproic Acid 2 Plat Hypo, Mus
Aminolevulinic acid 0.7 Alad Cere, Hypo, Lung
Amlexanox 3.5 S100a13, Fgf1 Aorta, BFAT, Kidney,
Liver, Lung
Amrinone 5 Heart Failure, Liver Pde3a, Pde4b BFAT, Cere, Heart,
Kidney, Mus, WFAT
Anagrelide 0.5 Chronic Myeloid Leukemia, Pde3a BFAT, Heart, Kidney,
ET, Leukemia Mus
Anakinra 4 Rheumatoid Arthritis Il1r1 Adr, Kidney, Lung, Mus
Ancrod 3 Clinical Trials Fga Liver
Aniracetam 1 Alzheimer's Disease Gria2, Htr2a, Gria3 Adr, BS, Heart, Lung
Apomorphine 0.66 Addiction, Anxiety, Drd4, Htr1b, Htr2a, Adr, BS, Cere, Heart,
Consumption, Parkinson's Htr2c, Drd3, Caly, Hypo, Kidney, Lung,
Disease, Erectile Adra2b, Htr1d, Adra2a WFAT
Dysfunction, Vomiting
Arbaclofen Placarbil 0.1 Gabbr1, Gabbr2 Kidney, Liver
Arbutamine 0.133 Adrb2, Adrb3, Adrb1 Adr, Aorta, BFAT,
Kidney, Lung, Mus
Ardeparin 3.3 Sodium Serpind1, Serpinc1 BS, Liver, Lung, WFAT
Aspartame 4.3 Consumption, Hearing, Tas1r2 Lung
Phenylketonuria, PKU
Atomoxetine 5 Hyperactivity, Hyperactivity Slc6a4, Grin3a, Adr, BS, Cere, Kidney,
Disorder Grin2b, Grin2c, Lung
Grin3b, Grin2d
Atracurium 0.33 Chrna2 BFAT
Atropine 3 Chrm3, Chrm2, Chrm4 Adr, BS, Heart, Kidney,
Liver, Lung
Avanafil 5.36 Erectile Dysfunction Pde5a Adr, Kidney
Axitinib 2.5 Breast, Breast Cancer, Flt1, Kdr, Flt4 Adr, BFAT, BS, Cere,
Cancer, Clinical Trials, Heart, Hypo, Kidney,
Magnetic Resonance Liver, Lung, Mus,
Imaging, MS WFAT
Azacitidine 4 Cancer, Chemotherapy Dnmt1 Adr, Lung
Baclofen 2.5 Alcohol Dependence, Gabbr1, Gabbr2 Kidney, Liver
Hiccups, Pain, Sleep
Banoxantrone 0.64 Top2a Hypo
Beclomethasone 2.8 Aphthous Ulcers, Colitis, Nr3c1 BFAT, Cere, Mus
Ulcerative Colitis, Hay
Fever, Inhalation, Psoriasis,
Rhinitis, Sinusitis
Benzonatate 3 Cough Scn5a Heart
Benzquinamide 1 Chrm3, Chrm2, Chrm4 Adr, BS, Heart, Kidney,
Liver, Lung
Betahistine 3 Balance Hrh3 Kidney
Betamethasone 5.6 Sodium Nr3c1 BFAT, Cere, Mus
Bezafibrate 1 LDL Cholesterol Ppara, Ppard, Pparg Adr, BFAT, Heart,
Kidney, Liver, Lung,
Mus, WFAT
Bifonazole 1 Cyp2b10 Aorta, BFAT, Liver,
Lung, WFAT
Bimatoprost 0.75 Glaucoma, Hypertension Ptger3, Ptgfr, Ptger1, Aorta, BFAT, Heart,
Akr1c18 Kidney, Lung, Mus,
WFAT
Binodenoson 0.166 Adora2a Heart, WFAT
Bleomycin 1.916 Cancer, Chemotherapy, Lig3, Lig1 Lung, WFAT
Testicular Cancer, Warts
Bosentan 5 Hypertension, Liver Ednra, Ednrb Adr, BFAT, BS, Heart,
Kidney, Lung, Mus
Brimonidine 2 Glaucoma, Hypertension, Adra2b, Adra2a Kidney, WFAT
Liver, Rosacea
Bromocriptine 2 Diabetes Mellitus, Drd4, Htr1b, Adra1d, Adr, BFAT, BS, Cere,
Parkinson's Disease, Liver, Adra1a, Htr7, Htr2a, Heart, Hypo, Kidney,
Type 2 Diabetes Htr2c, Drd3, Adra2b, Liver, Lung, Mus,
Adra1b, Htr1d, Adra2a WFAT
Budesonide 2 Allergies, Colitis, Ulcerative Nr3c1 BFAT, Cere, Mus
Colitis, COPD, Crohn's
Disease, Hay Fever,
Prevention, Rhinitis
Bumetanide 1 Chloride, Heart Failure, Slc12a2, Slc12a4, Cftr Aorta, BFAT, Cere,
Seizure Heart, Kidney, Liver,
Lung, Mus, WFAT
Bupivacaine 2.7 Dental Ptger1 Heart
Bupranolol 2 Adrb2, Adrb3, Adrb1 Adr, Aorta, BFAT,
Kidney, Lung, Mus
Buprenorphine 0.3 Addiction, Chronic Pain, Oprm1, Oprd1 BS, Lung
Liver, Pain
Cabazitaxel 4 Cancer, Prostate Cancer Tuba4a, Tubb1 BFAT, Cere, Hypo,
Kidney, Liver
Caffeine 3 Addiction, Cancer, Pde1a, Pde1b, Pde2a, Adr, Aorta, BFAT, BS,
Consumption, Dehydration, Pde3b, Pde5a, Pde8b, Cere, Heart, Hypo,
Parkinson's Disease, Adora1, Pde4a, Kidney, Liver, Lung,
Headache, Heart Disease, Pik3cb, Pde4b, Ryr1, Mus, WFAT
Insomnia, Pregnancy, Sleep, Pde10a, Pde7b, Pde3a,
Sodium Pde7a, Pde8a, Prkdc,
Pde9a, Adora2a,
Pik3ca, Pde4c, Pik3cd
Calcitriol 5 Vdr Adr, Aorta, BFAT
Capecitabine 0.75 Tyms Aorta
Captopril 2 Heart Failure, Hypertension Mmp2, Ace, Lta4h Adr, BS, Cere, Heart,
Hypo, Liver, Lung,
WFAT
Carbidopa 1 Parkinson's Disease Ddc Kidney, Liver
Carmustine 0.25 Chemotherapy, Crystals Gsr Adr, BFAT, BS, Mus
Cefazolin 1.8 Infusion Pon1 Adr, Mus
Cerivastatin 2 Renal Failure, Hmgcr Liver
Rhabdomyolysis
Cevimeline 5 Dry Mouth, Xerostomia Chrm3 Adr, BS, Kidney, Liver,
Lung
Chlorothiazide 0.75 Heart Failure, Intubation, Car4, Car2 Adr, BS, Heart, Kidney,
Pill, Sodium Liver, Lung
Ciclopirox 1.7 Atp1a1 BFAT, BS, Cere,
Kidney, Liver, Lung
Cinitapride 3 Htr2a BS, Heart, Lung
Ciprofloxacin 4 Clostridium Difficile, Top2a Hypo
Escherichia Coli,
Myasthenia Gravis,
Staphylococcus Aureus
Cisatracurium 0.366 Chrna2 BFAT
Besylate
Cladribine 5.4 Adenosine, Cancer, Hairy Pola1, Pole4, Pnp, Adr, Aorta, BS, Cere,
Cell Leukemia, Leukemia, Pole2, Rrm2b, Pole3, Hypo, Kidney, Liver,
Multiple Sclerosis Rrm1, Rrm2, Pole Lung, WFAT
Clevidipine 0.0166 Blood Pressure Cacna1c, Cacna1s, Adr, BFAT, Cere,
Cacna1d Kidney, Lung
Clofarabine 5.2 ALL, AML Pola1, Rrm1 Adr, Kidney
Clorazepate 2 Liver, Potassium Gabra3, Gabrg3, Adr, Aorta, BFAT, BS,
Gabrq, Gabrb1, Tspo, Cere, Hypo, Kidney,
Gabra2, Gabra5, Liver, Lung
Gabrb2, Gabrb3,
Gabra6, Gabrp
Clotiazepam 4 Anxiety, Liver, Sleep Gabra3, Gabrg3, Adr, Aorta, BFAT, BS,
Gabrb1, Gabra2, Cere, Heart, Hypo,
Gabrr2, Gabra5, Kidney, Lung, Mus,
Gabrb2, Gabrb3, WFAT
Gabrp, Gabrr1
Clotrimazole 2 Athlete's Foot, Itch, Jock Kcnn4 Kidney
Itch, Oral Candidiasis,
Ringworm, Thrush, Yeast
Infections
Cocaine 1 Balance, Sudden Cardiac Slc6a4, Chrm2, Scn5a Adr, BS, Heart, Kidney
Death, Potassium, Smoking,
Sodium
Codeine 3 Cough, Liver, Myocardial Oprm1, Oprd1 BS, Lung
Infarction
Colchicine 1 Gout, Pericarditis Tubb5, Tubb1 Kidney, Liver, WFAT
Conivaptan 5 Diabetes Insipidus, Heart Avpr1a, Avpr2 BFAT, Kidney, Liver,
Failure, Hyponatremia, Lung
Insipidus, Sodium
Corticotropin 0.25 Adrenal Insufficiency, Mc2r Adr, BFAT, Mus,
Circadian Rhythm, WFAT
Cushing's Syndrome,
Hypercortisolism, Rhythm,
Stress
Cosyntropin 0.25 Cushing's Syndrome, Mc2r Adr, BFAT, Mus,
Infusion WFAT
Creatine 3 Adenosine, Crystals, Slc6a8, Gamt, Ckm, Adr, Aorta, BFAT, BS,
Equilibrium, Liver, Ckb, Ckmt2, Ckmt1 Heart, Kidney, Lung
Supplements
Cromoglicic acid 1.3 Kcnma1 Adr, Liver
Cytarabine 0.166 Acute Myeloid Leukemia, Polb Kidney
ALL, AML, Cancer,
Chemotherapy, Infusion,
Leukemia, Liver,
Malignancy, WS
Dacarbazine 5 Cancer, Chemotherapy, Pola2, Pgd Aorta, BFAT, Kidney,
Infusion, Liver, Malignant Liver, Lung, Mus,
Melanoma, Melanoma WFAT
Dalfampridine 3.5 Multiple Sclerosis, Kcna1, Kcnd2, Kcna4 Aorta, BFAT, Cere,
Potassium Heart, Kidney
Dantrolene 4 Cerebral Palsy, Ryr1 BFAT
Hyperthermia, Malignant
Hyperthermia, Liver,
Multiple Sclerosis, Sodium
Dapoxetine 1 Htr1b, Htr2c Adr, BS, Cere
Dasatinib 3 ALL, BMS, Cancer, CML, Stat5b, Epha2, Abl1, Aorta, BFAT, Heart,
Leukemia, Liver, Prostate Src, Kit, Pdgfrb, Fyn, Hypo, Kidney, Liver,
Cancer Abl2, Lck Lung, Mus
Decitabine 0.51 Acute Myeloid Leukemia, Dnmt1 Adr, Lung
AML, Leukemia
Defibrotide 1 Adora1, Adora2a, Aorta, BFAT, Heart,
Adora2b Liver, Lung, WFAT
Denileukin diftitox 1.166 Leukemia, Neuropathy, Il2rg, Il2rb, Il2ra Adr, Heart, Liver, Lung,
Optic Neuropathy Mus
Desmopressin 1 Bedwetting, Diabetes Avpr1a, Avpr2 BFAT, Kidney, Liver,
Insipidus, Insipidus Lung
Dexmedetomidine 2 Depression, Infusion Adra2a WFAT
Dexmethylphenidate 2 Hyperactivity, Hyperactivity Slc6a4 Adr, Kidney
Disorder, Psychosis
Dexrazoxane 2.5 Top2a, Top2b Hypo, Kidney, Mus
Dextromethorphan 3 CF, COLD, Cold, Common Sigmar1, Grin3a, Adr, Aorta, BFAT, BS,
Cold, Cough, Liver, Pain Slc6a4, Chrnb4, Cere, Hypo, Kidney,
Chrna2, Chrna3, Liver, Lung, WFAT
Oprm1, Chrna4,
Chrnb2, Oprd1
Dezocine 2.2 Oprm1 BS
Diazepam 1 Anxiety, Depression, Gabra3, Gabrg3, Adr, Aorta, BFAT, BS,
Insomnia, Restless Legs, Gabrq, Gabrb1, Tspo, Cere, Heart, Hypo,
Liver, Muscle Spasms, Gabra2, Gabrr2, Kidney, Liver, Lung,
Seizure, Restless Legs Gabra5, Gabrb2, Mus, WFAT
Syndrome, Tetanus Gabrb3, Gabra6,
Gabrp, Gabrr1
Diclofenac 2 Aches, Gallstones, NSAID, Ptgs2, Scn4a, Kcnq2, Aorta, BFAT, BS, Cere,
Pain, Potassium, Sodium Kcnq3, Ptgs1 Heart, Kidney, Lung
Diltiazem 3 Arrhythmia, Hypertension, Cacng1 BFAT
Mammary Gland, Migraine
Dinoprost 3 Amniotic Fluid, Ptgfr Heart, Lung, Mus
Tromethamine Endometriosis, Stress
Dinoprostone 0.0833 Ptger2, Ptger3, Ptger1, Aorta, BFAT, Heart,
Ptger4 Kidney, Lung, WFAT
Diphenidol 4 Chrm3, Chrm2 Adr, BS, Heart, Kidney,
Liver, Lung
Dipyridamole 0.66 Pde5a, Pde4a, Pde10a, Adr, Aorta, BFAT,
Ada Cere, Heart, Hypo,
Kidney, Liver, Lung,
Mus
Dobutamine 0.033 Dobutamine, Heart Failure, Adrb2, Adrb1 Adr, Kidney, Lung, Mus
Shock
Dopamine 0.033 Anti-nausea, Attention Drd4, Slc6a4, Htr7, Adr, BFAT, Cere, Hypo,
Deficit Hyperactivity Dbh, Drd3 Kidney
Disorder, Digestive System,
Parkinson's Disease, Heart
Failure, Hyperactivity,
Hyperactivity Disorder,
Restless Legs, RLS,
Schizophrenia, Shock,
Sodium, Restless Legs
Syndrome, Tremor
Dronabinol 4 Cnr1, Cnr2 Adr, Mus, WFAT
Droperidol 1.4 Adra1a BFAT, Heart, Kidney,
Lung, Mus, WFAT
Drotrecogin alfa 5.5 Sepsis Serpine1, Pf4, Ggcx, Adr, Aorta, BFAT, BS,
Procr, Cp, Thbd, F8, Cere, Heart, Hypo,
F5, Serpina5 Kidney, Liver, Lung,
Mus, WFAT
Droxidopa 2 Adra1d, Adrb2, Adrb3, Adr, Aorta, BFAT,
Adra1a, Adra2b, Heart, Kidney, Liver,
Adra1b, Pah, Adrb1, Lung, Mus, WFAT
Adra2a
Dydrogesterone 5 Dysfunctional Uterine Pgr Aorta
Bleeding, Endometriosis,
Hormone Replacement
Therapy, HRT, Infertility,
Menopause, Premenstrual
Syndrome
Dyphylline 2 Pde4a, Adora1, Pde4b, Aorta, BFAT, BS, Cere,
Pde7a, Pde7b, Heart, Hypo, Kidney,
Adora2a, Pde4c Liver, Lung, Mus,
WFAT
Eletriptan 4 Headache, Migraine Htr1b, Htr7, Htr1d Adr, BFAT, BS, Lung
Enalapril 2 Blood Pressure, Heart Ace Heart, Lung
Failure, Hypertension
Encainide 1 Scn5a Heart
Enoxacin 3 Cancer, Cystitis, Gonorrhea, Top2a Hypo
Insomnia, Sexually
Transmitted Diseases,
Urinary Tract Infection
Enoxaparin 4.5 Sodium Serpinc1 Liver
Enoximone 4 Heart Failure, Liver Pde3a BFAT, Heart, Kidney,
Mus
Enprofylline 1.9 Adenosine, Chronic Pde4a, Adora1, Pde4b, Aorta, BFAT, Cere,
Obstructive Lung Disease Adora2a, Adora2b Heart, Hypo, Liver,
Lung, Mus, WFAT
Enzalutamide 1 Breast, Breast Cancer, Ar Aorta, BFAT, BS,
Cancer, Prostate Cancer, Kidney
Prostate Specific Antigen,
PSA
Ephedrine 3 Hypotension Adra1a, Ache BFAT, Heart, Kidney,
Lung, Mus, WFAT
Epinephrine 0.033 Hypertension, Stress Adrb2, Adra1d, Adrb3, Adr, Aorta, BFAT,
Adra1a, Adra2b, Heart, Kidney, Liver,
Adra1b, Pah, Adrb1, Lung, Mus, WFAT
Adra2a
Epirubicin 3 Breast, Breast Cancer, Top2a Hypo
Cancer, Chemotherapy,
Gastric Cancer, Lung
Cancer, Lymphomas,
Ovarian Cancer
Eplerenone 4 Heart Failure, Myocardial Nr3c2 Heart, Lung, Mus
Infarction, Potassium
Eprosartan 5 Blood Pressure, Agtr1a Adr, Heart, Kidney,
Hypertension Liver, Mus
Eptifibatide 2.5 Itgb3 Lung
Ergoloid mesylate 3.5 Adra1d, Slco2b1, Adr, Aorta, BFAT, BS,
Htr1b, Gabra3, Cere, Heart, Hypo,
Gabrg3, Gabrq, Kidney, Liver, Lung,
Adra1a, Htr7, Gabrb1, Mus, WFAT
Htr2a, Gabra2, Htr2c,
Gabra5, Gabrb2,
Gabrb3, Adra2b,
Adra1b, Gabra6,
Htr1d, Htr6, Gabrp,
Adra2a
Ergonovine 1 Adra1a BFAT, Heart, Kidney,
Lung, Mus, WFAT
Ergotamine 2 Migraine Htr1b, Adra1d, Adr, BFAT, BS, Cere,
Adra1a, Htr2a, Htr2c, Heart, Kidney, Liver,
Adra2b, Adra1b, Lung, Mus, WFAT
Htr1d, Adra2a
Esmolol 2 Adrb1 Lung
Esomeprazole 1 Dyspepsia, Gastroesophageal Atp4a Liver
Reflux Disease, Liver, Peptic
Ulcer, Reflux, Ulcer
Ethinamate 2.5 Insomnia Car2 BS, Kidney, Liver, Lung
Ethionamide 2 Extensively Drug-Resistant Inha BS, Cere, Heart
Tuberculosis, TB, Drug-
Resistant Tuberculosis
Ethopropazine 1 Grin3a, Chrm2 Adr, BS, Heart
Ethotoin 3 Epilepsy Scn5a Heart
Ethoxzolamide 2.5 Epilepsy, Glaucoma, Peptic Car4, Car2 Adr, BS, Heart, Kidney,
Ulcer, Ulcer Liver, Lung
Etidronic acid 1 Ptprs, Atp6v1a Cere, Hypo, Liver,
Lung, Mus, WFAT
Etodolac 1 Liver, NSAID Rxra, Ptgs2, Ptgs1 Adr, Aorta, BFAT,
Heart, Kidney, Liver,
Lung
Etomidate 1.25 Emergency Medicine, Gabra3, Gabrg3, Adr, Aorta, BFAT, BS,
Intubation, Liver Gabrq, Gabrb1, Cere, Hypo, Kidney,
Gabra2, Gabra5, Liver, Lung
Gabrb2, Gabrb3,
Adra2b, Gabra6,
Gabrp
Etoposide 4 Liver Top2a, Top2b Hypo, Kidney, Mus
Fenoldopam 5 Liver, Sodium Adra1d, Adra1a, Adr, BFAT, Heart,
Adra2b, Adra1b, Kidney, Liver, Lung,
Adra2a Mus, WFAT
Fenoprofen 3 Rheumatoid Arthritis, Pain Ptgs2, Ptgs1 Aorta, Heart, Kidney,
Lung
Filgrastim 3.5 E. Coli, Escherichia Coli Csf3r, Elane Lung, WFAT
Finasteride 4.5 Baldness, Benign Prostatic Srd5a1, Akr1d1, BFAT, Cere, Kidney,
Hyperplasia, Birth Defects, Srd5a2 Liver
BPH, Liver
Flucytosine 2.4 Dnmt1 Adr, Lung
Fludrocortisone 3.5 Ar, Nr3c1, Nr3c2 Aorta, BFAT, BS, Cere,
Heart, Kidney, Lung,
Mus
Flumazenil 4 Hypersomnia Gabra3, Gabrg3, Adr, Aorta, BFAT, BS,
Gabrq, Gabrb1, Cere, Hypo, Kidney,
Gabra2, Gabra5, Liver, Lung
Gabrb2, Gabrb3,
Gabra6, Gabrp
Flunisolide 1.8 Allergic Rhinitis, Inhalation, Nr3c1 BFAT, Cere, Mus
Rhinitis
Fluocinolone 1.3 Liver, Skin Inflammation Nr3c1 BFAT, Cere, Mus
Acetonide
Fluorouracil 0.166 Cancer, Infusion, Liver Tyms Aorta
Flurazepam 2.3 Anxiety, Dental, Insomnia, Gabra3, Gabrg3, Adr, Aorta, BFAT, BS,
Liver, Pregnancy Gabrq, Gabrb1, Cere, Heart, Hypo,
Gabra2, Gabrr2, Kidney, Liver, Lung,
Gabra5, Gabrb2, Mus, WFAT
Gabrb3, Gabra6,
Gabrp, Gabrr1
Flurbiprofen 4.7 Cancer, Clinical Trials, Ptgs2, Ptgs1 Aorta, Heart, Kidney,
Liver, Pain Lung
Fluvastatin 3 Hepatitis, Hepatitis C, Hmgcr Liver
Hypercholesterolemia
Fosphenytoin 0.25 Liver, Sodium Scn5a Heart
Furosemide 2 Edema, Heart Failure, Car2 BS, Kidney, Liver, Lung
LASIK
Fusidic Acid 5 Sodium Cat Adr, Liver, Lung, Mus
Gabapentin 5 Anxiety, Anxiety Disorder, Grin3a, Adora1, Adr, Aorta, BFAT, BS,
Bipolar Disorder, Diabetic Cacna2d1, Grin2b, Cere, Heart, Hypo,
Neuropathy, Epilepsy, Grin2c, Cacna1b, Kidney, Liver, Lung,
Insomnia, Neuropathic Pain, Grin3b, Grin2d WFAT
Neuropathy, Pain, Restless
Leg Syndrome
Gallium nitrate 1 Atp6v1b2, Rrm2, Il1b Heart, Kidney, Liver,
Lung
Galsulfase 0.15 Plin3 BS, Cere, Heart, Liver
Gamma 0.5 Cataplexy, Depression, Gabrb1 BFAT, BS, Cere
Hydroxybutyric Acid Excessive Daytime
Sleepiness, Insomnia,
Narcolepsy, Potassium,
Rape, Sleepiness, Sodium
Ganaxolone 1.3 Gabra3, Gabra2, Adr, Aorta, BFAT, BS,
Gabra5, Gabra6 Cere, Hypo, Kidney,
Liver
Gemcitabine 0.7 Chemotherapy Tyms, Rrm1, Cmpk1 Aorta, Kidney, WFAT
Gemfibrozil 1.5 Ppara Adr, BFAT, Heart,
Kidney, Liver, Lung,
WFAT
Gentamicin 3 E. Coli, Escherichia Coli Lrp2 Kidney, Lung
Glimepiride 5 Type 2 Diabetes Kcnj11, Abcc8, Kcnj1 BFAT, Cere, Hypo,
Kidney
Glipizide 2 Liver, Potassium Abcc8, Pparg Hypo, Kidney, Mus
Glyburide 1.4 Liver Abcc9, Abca1, Kcnj8, Adr, Aorta, BFAT, BS,
Cpt1a, Kcnj11, Kcnj5, Cere, Heart, Hypo,
Abcc8, Kcnj1, Cftr, Kidney, Liver, Lung,
Abcb11 Mus, WFAT
Glycodiazine 4 Abcc8, Kcnj1 Hypo, Kidney
Glycopyrrolate 0.6 Chrm3, Chrm2 Adr, BS, Heart, Kidney,
Liver, Lung
Gonadorelin 0.033 Gnrhr Adr, BFAT, Lung
Goserelin 4 Breast, Cancer, Prostate Gnrhr Adr, BFAT, Lung
Cancer
Heparin 1.5 Dialysis, Liver, Sodium Selp, Serpinc1 BFAT, Liver
Heroin 0.166 Hepatitis, Inhalation, Oprm1, Oprd1 BS, Lung
Pregnancy, Smoking
Hexylcaine 0.166 Convulsion, Headache, Scn5a Heart
Sodium, Tinnitus
Hydralazine 3 Blood Pressure, P4ha1, Aoc3 Adr, Aorta, BFAT, BS,
Hypertension Cere, Heart, Hypo,
Kidney, Lung, Mus,
WFAT
Hydrochlorothiazide 5.6 Blood Pressure, Car4, Car2, Car12, Adr, BS, Cere, Heart,
Hypertension, Pregnancy Car9 Kidney, Liver, Lung
Hydrocodone 1.25 Cough Oprm1, Oprd1 BS, Lung
Hydroflumethiazide 2 Car4, Atp1a1, Car2, Adr, BFAT, BS, Cere,
Car12, Car9 Heart, Kidney, Liver,
Lung
Hydromorphone 2.6 Swallowing Oprm1, Oprd1 BS, Lung
Hydroxyurea 3 Rrm1 Kidney
Hyoscyamine 2 Chrm3, Chrm2, Chrm4 Adr, BS, Heart, Kidney,
Liver, Lung
Ibritumomab 0.8 C1qa, C1qc, C1qb, Adr, Heart, Kidney,
Ms4a1, Fcgr2b, Fcgr3, Liver, Mus, WFAT
Fcgr4, C1rb
Ibuprofen 2 CP, Febrile Seizures, Bcl2, Ptgs2, Thbd, Adr, Aorta, BFAT, BS,
NSAID, Nursing, Pain, Ptgs1, Plat, Pparg, Cere, Heart, Hypo,
Pediatrics Cftr Kidney, Lung, Mus,
WFAT
Icatibant 1.4 Angioedema Anpep BS, Liver
Idursulfase 0.733 Plin3 BS, Cere, Heart, Liver
Iloprost 0.333 Blood Pressure, Pde4a, Pde4b, Ptger1, Aorta, BFAT, Cere,
Hypertension, Inhalation, Plat, Pde4c Heart, Hypo, Liver,
Pulmonary Hypertension, Lung, Mus, WFAT
Raynaud's Phenomenon
Indomethacin 4.5 Glo1, Ppara, Ptgs2, Adr, Aorta, BFAT,
Ptgs1, Pparg Heart, Kidney, Liver,
Lung, Mus, WFAT
Insulin Detemir 5 Hemoglobin, Hypoglycemia, Insr Liver, Lung
Type 2 Diabetes
Insulin Glulisine 0.7 Hyperglycemia Insr Liver, Lung
Insulin Lispro 1 Igflr, Insr Kidney, Liver, Lung
Interferon Alfa-2a, 2 Ifnar2 Adr, Cere, Liver, Mus
Recombinant
Interferon Alfa-2b, 2 Ifnar2 Adr, Cere, Liver, Mus
Recombinant
Interferon alfacon-1 1.3 Ifnar2 Adr, Cere, Liver, Mus
Interferon alfa-n1 1.2 Ifnar2 Adr, Cere, Liver, Mus
Ipratropium bromide 2 Chrm3, Chrm2 Adr, BS, Heart, Kidney,
Liver, Lung
Iron Dextran 5 Hba-a1, Fth1 Adr, Kidney, Liver
Isoniazid 0.5 Liver, Prevention Inha BS, Cere, Heart
Isosorbide Dinitrate 1 Npr1 Adr, Aorta
Isosorbide 5 Blood Pressure Gucy1a2 Adr, Kidney, Lung, Mus
Mononitrate
Ketamine 2.5 Allergies, Complex Regional Grin3a, Chrm3, Htr1b, Adr, BS, Cere, Heart,
Pain Syndrome, Emergency Tacr1, Oprm1, Chrm2, Kidney, Liver, Lung
Medicine, Liver, Pain, Htr2a, Htr2c, Oprd1,
Respiration Chrm4, Htr1d
Ketobemidone 2.42 Cancer, Pain Grin3a, Oprm1, Adr, BS, Cere, Kidney,
Grin2b, Grin2c, Lung
Grin3b, Oprd1, Grin2d
Ketoconazole 2 Dandruff, Dermatitis, Liver Cyp19a1, Ar Adr, Aorta, BFAT, BS,
Kidney
Ketoprofen 1.1 NSAID Ptgs2, Ptgs1 Aorta, Heart, Kidney,
Lung
Ketorolac 2.5 Allergies, Allergy, Liver, Ptgs2, Ptgs1 Aorta, Heart, Kidney,
NSAID, Pain Lung
Lansoprazole 1.5 Heartburn, Intubation, Liver Atp4a Liver
Latanoprost 0.283 Glaucoma, Hypertension Ptgfr Heart, Lung, Mus
L-DOPA 0.833 Drd4, Drd3 Adr, Hypo
Lenalidomide 3 Multiple Myeloma, Cdh5, Ptgs2 Aorta, BFAT, Heart,
Myeloma Hypo, Liver, Lung, Mus
Leptin 0.415 Obese, Obesity Lepr Lung
Leuprolide 3 Gnrhr Adr, BFAT, Lung
Levallorphan 1 Depression Oprm1 BS
Levamisole 4.4 Agranulocytosis, Cancer, Chrna3 BS, Hypo
Chemotherapy, Colon
Cancer, Head and Neck
Cancer, Liver, Melanoma,
Neck Cancer, Prevention
Levosimendan 1 Heart Failure Kcnj8, Kcnj11, Pde3a, Adr, BFAT, Cere, Heart,
Tnnc1 Kidney, Liver, Mus
Lidocaine 1.8166 Dental, Liver, Pain Scn5a, Egfr Heart, Lung
Lornoxicam 3 NSAID, Pain Ptgs2, Ptgs1 Aorta, Heart, Kidney,
Lung
Losartan 1 Blood Pressure, Agtr1a Adr, Heart, Kidney,
Hypertension, Myocardial Liver, Mus
Infarction, Nursing,
Potassium, Prevention, Renal
Disease, Type 2 Diabetes
Lovastatin 5.3 Hypercholesterolemia, Itga1, Hdac2, Hmgcr Adr, Kidney, Liver,
Hyperlipidemia Lung
Loxapine 4 Inhalation, Liver, Htr1b, Chrm3, Drd4, Adr, BFAT, BS, Cere,
Schizophrenia Slc6a4, Htr7, Adra1a, Heart, Hypo, Kidney,
Htr2a, Chrm2, Htr2c, Liver, Lung, Mus,
Drd3, Adra2b, Adra1b, WFAT
Htr1d, Htr6, Adrb1,
Chrm4, Adra2a
Lubiprostone 0.9 Constipation, Irritable Bowel Clcn2 Adr, BS, Cere, Heart,
Syndrome Kidney, WFAT
Lumiracoxib 4 Liver, NSAID Ptgs2, Ptgs1 Aorta, Heart, Kidney,
Lung
Mebendazole 2.5 AS Tuba1a BFAT, Heart, Kidney,
WFAT
Mecasermin 2 Igfbp3, Igf2r, Igf1r, Adr, Aorta, BFAT,
Insr Hypo, Kidney, Liver,
Lung
Mefenamic acid 2 Headache, Liver, Ptgs2, Ptgs1 Aorta, Heart, Kidney,
Menstruation, Migraine, Lung
Migraine Headache, NSAID,
Pain, Prevention
Melatonin 0.5833 Circadian Rhythm, Clinical Calr, Esr1, Rorb, Adr, Aorta, BFAT, BS,
Trials, Sleep Disorders, Nqo2, Mtnr1a Cere, Heart, Hypo,
Insomnia, Liver, Rhythm, Kidney, Liver, Lung,
Sleep, TIPS Mus, WFAT
Mesalazine 5 Colitis, Ulcerative Colitis, Ptgs2, Ptgs1, Pparg, Aorta, Heart, Kidney,
Crohn's Disease, Liver Chuk, Ikbkb Liver, Lung, Mus
Methamphetamine 4 Addiction, Attention Deficit Slc6a4, Maoa, Slc18a1, Adr, Kidney, Liver,
Hyperactivity Disorder, Adra2b, Maob, Adra2a Lung, Mus, WFAT
Drug Addiction,
Hyperactivity, Hyperactivity
Disorder, Inhalation,
Obesity, Psychosis,
Rhabdomyolysis, Substance
Abuse
Methimazole 5 Agranulocytosis, Graves' Tpo Liver
Disease, Hyperthyroidism,
Liver
Methsuximide 1.4 Cacna1g Aorta, Lung, WFAT
Methyldopa 1.75 Hypertension, Liver, PIH, Ddc, Adra2a Kidney, Liver, WFAT
Pregnancy
Methylphenidate 3 Attention Deficit Slc6a4 Adr, Kidney
Hyperactivity Disorder,
Hyperactivity, Hyperactivity
Disorder, Liver, Narcolepsy,
Postural Orthostatic
Tachycardia Syndrome,
Recall, Tachycardia
Methylprednisolone 1 Infusion, Liver Nr3c1 BFAT, Cere, Mus
Metocurine Iodide 3 Chrna2 BFAT
Metoprolol 3 Hypertension, Liver Adrb2, Adrb1 Adr, Kidney, Lung, Mus
Metyrosine 3.4 Th BFAT
Midazolam 1.8 Epilepsy, Insomnia, Liver, Gabra3, Gabrg3, Adr, Aorta, BFAT, BS,
Seizures in Children Gabrq, Gabrb1, Cere, Heart, Hypo,
Gabra2, Gabrr2, Kidney, Liver, Lung,
Gabra5, Gabrb3, Mus, WFAT
Gabrb2, Gabra6,
Gabrp, Gabrr1
Miglitol 2 Diabetes Mellitus, Gaa Aorta, Kidney
Hyperglycemia
Milrinone 2.3 Arrhythmia, CHF, Heart Pde3a BFAT, Heart, Kidney,
Failure, Infusion Mus
Minoxidil 4.2 Baldness, Hair Loss, Ptgs1, Kcnj1 Heart, Kidney, Lung
Prevention
Misoprostol 0.33 Gastric Ulcer, Peptic Ulcer, Ptger3, Ptger2, Ptger4 Aorta, BFAT, Heart,
Ulcer Kidney, Lung, WFAT
Mivacurium 1.7 Chloride Chrm3, Bche, Chrna2, Adr, BFAT, BS, Heart,
Chrm2 Kidney, Liver, Lung
Moclobemide 1 Anxiety, Blood Pressure, Maoa Adr, Kidney, WFAT
Depression, LP
Moexipril 1 Heart Failure, Hypertension Ace, Ace2 Heart, Lung
Mometasone 5.8 Nr3c1 BFAT, Cere, Mus
Montelukast 2.7 Allergies, Allergy, Asthma Cysltr1 Heart
Medications, Liver
Moricizine 2 Scn5a Heart
Morphine 2 Addiction, Chronic Pain, Oprm1, Oprd1 BS, Lung
Depression, Inhalation, Pain,
Sleep, Smoking
Muromonab 0.8 C1qa, C1qc, C1qb, Adr, Heart, Kidney,
Fcgr2b, Fcgr3, Cd3e, Liver, Lung, Mus,
Cd3d, Cd3g, Fcgr4, WFAT
C1rb
Nabilone 2 Antiemetics, Chemotherapy, Cnr1, Cnr2 Adr, Mus, WFAT
Chronic Pain, Chronic Pain
Management, Liver,
Multiple Sclerosis, Nausea
and Vomiting, Neuropathic
Pain, Pain, Pain
Management, Vomiting
Nafarelin 3 Endometriosis, Fibroids, Gnrhr Adr, BFAT, Lung
IVF, Puberty, Uterine
Fibroids
Nalbuphine 5 Oprm1, Oprd1 BS, Lung
Naloxone 0.5 Addiction, Depression, Creb1, Esr1, Oprm1, Adr, Aorta, BFAT, BS,
Hypotension, Liver, Pain Tlr4, Oprd1 Cere, Heart, Hypo,
Kidney, Liver, Lung,
Mus, WFAT
Naltrexone 4 Alcohol Dependence, Oprm1, Oprd1 BS, Lung
Constipation
Naratriptan 5 Liver, Migraine Htr1b, Htr1d Adr, BS, Lung
Nateglinide 1.5 Type 2 Diabetes Abcc8, Pparg Hypo, Kidney, Mus
Nedocromil 3.3 Breathing, Inhalation, Hsp90aa1, Cysltr2, Adr, Aorta, BFAT, BS,
Sodium Cysltr1 Cere, Heart, Hypo,
Kidney, Liver, Lung,
Mus, WFAT
Nefazodone 2 Liver, Liver Transplant Slc6a4, Adra1a, Htr2a, Adr, BFAT, BS, Cere,
Htr2c, Adra1b, Adra2a Heart, Kidney, Liver,
Lung, Mus, WFAT
Nesiritide 0.3 Heart Failure Npr1, Npr2, Npr3 Adr, Aorta, Cere, Heart,
Kidney, Lung
Niacin 0.33 Anemia, Atherosclerosis, Niacr1 Adrenal
Crystals, Necropsy,
Tiredness
Nifedipine 2 Cancer, Hypertension, Cacna1c, Cacna1h, Adr, Aorta, BFAT,
Pulmonary Hypertension, Kcna1, Cacna2d1, Cere, Kidney, Lung
Raynaud's Phenomenon, Cacna1s, Cacna1d
Tetanus
Niflumic Acid 2.5 Ptgs2, Pla2g4a, Ptgs1 Aorta, Heart, Hypo,
Kidney, Lung
Nimesulide 1.8 NSAID, Pain Ptgs2, Ltf Aorta, Lung
Nimodipine 1.7 Blood Pressure, Cacna1c, Ahr, Adr, Aorta, BFAT,
Hypertension Cacna1s, Cacnb1, Cere, Heart, Kidney,
Cacna1d, Cacnb3, Lung, Mus, WFAT
Cacnb4, Nr3c2
Nitazoxanide 3.5 Por Adr, Aorta, BFAT, BS,
Cere, Heart, Hypo,
Kidney, Liver, Lung,
WFAT
Nitroglycerin 0.05 Cancer, Heart Failure, Npr1 Adr, Aorta
Prostate Cancer
Nitroprusside 0.033 Sodium Npr1 Adr, Aorta
Norfloxacin 3 Chemotherapy, Cystitis, Top2a Hypo
Liver, Neuropathy,
Peripheral Neuropathy,
Prostatitis, Sexually
Transmitted Diseases
Olopatadine 3 Allergies, Allergy, S100a1, S100a13, Adr, Aorta, Liver,
Conjunctivitis S100b WFAT
Olsalazine 0.9 Colitis, Ulcerative Colitis Tpmt Kidney
Omeprazole 0.5 Dyspepsia, Gastroesophageal Atp4a Liver
Reflux Disease, Liver, Peptic
Ulcer, Reflux, Ulcer
Ondansetron 5.7 Cancer, Chemotherapy, Htr1b, Oprm1 Adr, BS
Liver, Motion Sickness,
Nausea and Vomiting,
Radiation Therapy,
Vomiting
Orlistat 1 Blood Pressure, Obese, Fasn Hypo, Kidney, Liver,
Obesity, Overweight, Pill, Mus, WFAT
Type 2 Diabetes
Oseltamivir 1 Chemotherapy, Clinical Neu1, Neu2, Ces1d Aorta, BFAT, Cere,
Trials, EA, Swine Flu, Heart, Kidney, Liver,
Influenza, Liver, MS, Lung
Prevention, Vomiting
OspA lipoprotein 1.2 Tlr2 Kidney
Oxandrolone 0.55 Ar Aorta, BFAT, BS,
Kidney
Oxcarbazepine 2 Anxiety, Anxiety Disorder, Scn5a Heart
Epilepsy, Tics
Oxprenolol 1 Blood Pressure, Adrb2, Adrb1 Adr, Kidney, Lung, Mus
Hypertension, Liver,
Mammary Gland
Oxtriphylline 3 Pde4a, Adora1, Pde3a, Aorta, BFAT, Cere,
Adora2a, Hdac2 Heart, Hypo, Kidney,
Liver, Lung, Mus,
WFAT
Oxycodone 4.5 NSAID, Pain Oprm1, Oprd1 BS, Lung
Oxymorphone 1.3 Liver Oprm1, Oprd1 BS, Lung
Oxytocin 0.0166 Anxiety, Intimacy, Nipple, Oxt Kidney
WS
Pancuronium 1.5 Chrm3, Chrna2, Adr, BFAT, BS, Heart,
Chrm2 Kidney, Liver, Lung
Pantoprazole 1 Liver Atp4a Liver
Papaverine 0.5 Erectile Dysfunction Pde4b, Pde10a BFAT, Cere, Heart,
Mus, WFAT
Paricalcitol 4 Vdr Adr, Aorta, BFAT
PCK3145 0.35 Rpsa Liver, Lung
Pegaptanib 3 Age-Related Macular Nrp1 BFAT, Heart, Kidney,
Degeneration, Macular Liver, Lung, Mus
Degeneration, Sodium
Pemetrexed 3.5 Cancer, Chemotherapy, Tyms, Gart, Atic Aorta, Kidney, Liver,
Lung Cancer, Mesothelioma Lung, WFAT
Pentagastrin 0.166 Carcinoid Syndrome Cckbr BS
Pentazocine 2 Liver, Pain Sigmar1, Oprm1 Adr, Aorta, BS, Kidney,
Liver, Lung, WFAT
Pentobarbital 5 Liver, Sodium Gabra3, Gria2, Adr, Aorta, BFAT, BS,
Gabrg3, Grin3a, Cere, Hypo, Kidney,
Gabrq, Gabrb1, Liver, Lung
Gabra2, Grin2b,
Gabra5, Chrna4,
Grin2c, Gabrb2,
Gabrb3, Grin3b,
Gabra6, Gabrp,
Grin2d
Pentosan Polysulfate 4.8 Fgf4, Fgf1, Fgf2 Adr, Aorta, BFAT, BS,
Kidney, Liver, Lung,
WFAT
Pentostatin 5.7 Chronic Lymphocytic Ada Hypo
Leukemia, Leukemia, Liver
Pentoxifylline 0.4 CP Pde5a, Nt5e, Adora1, Adr, Aorta, BFAT,
Pde4a, Pde4b, Cere, Heart, Hypo,
Adora2a Kidney, Liver, Lung,
Mus, WFAT
Perhexiline 2 Consumption Cpt1a, Cpt2 Adr, Aorta, BFAT,
Cere, Heart, Hypo,
Kidney, Liver, Lung,
Mus
Perindopril 1.2 Blood Pressure, Coronary Ace Heart, Lung
Artery Disease, Heart Failure
Pethidine 1 Chrm3, Slc6a4, Adr, BS, Cere, Heart,
Grin2b, Chrm2, Kidney, Liver, Lung
Oprm1, Grin2c,
Grin2d, Chrm4
Phenelzine 1.2 Liver Maoa, Abat, Gpt, Gpt2, Adr, Aorta, BFAT, BS,
Aoc3, Maob Cere, Hypo, Kidney,
Liver, Lung, Mus,
WFAT
Phenindione 5 Breast Vkorc1 Adr, BFAT
Phentolamine 0.3166 Adra1a, Adra2a BFAT, Heart, Kidney,
Lung, Mus, WFAT
Phenylephrine 2.1 Blood Pressure, Liver Adra1d, Adra1a, Adr, BFAT, Heart,
Adra1b Kidney, Liver, Lung,
Mus, WFAT
Phenylpropanolamine 2.1 COLD, Cold, Cough, Adrb2, Adra1a, Adrb1, Adr, BFAT, Heart,
Urinary Incontinence Adra2a Kidney, Lung, Mus,
WFAT
Pilocarpine 0.76 Cancer, Dry Mouth, Chrm3, Chrm2 Adr, BS, Heart, Kidney,
Glaucoma, Head and Neck Liver, Lung
Cancer, Neck Cancer, Oral
Surgery, Radiotherapy,
Xerostomia
Pindolol 3 Liver Adrb2, Htr1b, Adrb1 Adr, BS, Kidney, Lung,
Mus
Pioglitazone 3 Liver Pparg Kidney, Mus
Pirfenidone 2 Furin BFAT, Kidney
Plerixafor 4.4 Cancer, Stem Cells Cxcr4 BFAT, Heart, Mus,
WFAT
Podofilox 1 Tuba4a, Top2a, Tubb5 BFAT, Cere, Hypo,
Kidney, Liver, WFAT
Pralidoxime 1.233 Chloride Bche, Ache Adr, BFAT, Kidney
Pramlintide 0.8 BMS, Diabetes Mellitus Ramp1, Ramp3 BFAT, Lung
Prazosin 2 Anxiety, Blood Pressure, Adra1d, Adra1a, Adr, BFAT, Heart,
Panic Disorder, PTSD Kcnh2, Adra2b, Kidney, Liver, Lung,
Adra1b, Kcnh6, Kcnh7, Mus, WFAT
Adra2a
Prednisolone 2 Hepatitis Nr3c1 BFAT, Cere, Mus
Prednisone 2 Cancer, Fatty Liver, Liver Nr3c1, Hsd11b1 BFAT, Cere, Heart,
Liver, Lung, Mus
Preotact 1.5 Escherichia Coli, Menopause Pth1r Liver
Primaquine 3.7 Liver Krt7, Nqo2 Aorta, Hypo, Kidney,
Liver, Lung, WFAT
Primidone 3 Anemia, Bipolar Disorder, Gabra3, Gria2, Adr, Aorta, BFAT, BS,
Birth Defects, Cerebral Gabrg3, Gabrq, Cere, Hypo, Kidney,
Palsy, Depression, Gabrb1, Gabra2, Liver, Lung
Depressive Disorder, Gabra5, Chrna4,
Essential Tremor, Liver, Gabrb2, Gabrb3,
Migraine, Neuropathic Pain, Gabra6, Gabrp
Pain, Seizure, Sodium,
Tonic-Clonic Seizure,
Tremor, Trigeminal
Neuralgia
Procainamide 2.5 Arrhythmia, Liver Dnmt1, Scn5a Adr, Heart, Lung
Procaine 0.1283 Dental, Pain, Sodium Grin3a, Kcnmb2, Adr, BFAT, BS, Heart,
Kcnn1, Maoa, Chrna2, Kidney, Liver, Lung,
Kcnn3, Kcnmb1, Mus, WFAT
Kcnn4, Maob
Progabide 4 Epilepsy Gabbr1 Kidney
Propafenone 2 Scn5a, Kcnh2 Heart, Lung, WFAT
Propofol 1 Emergency Medicine, Liver, Gabra3, Gabrg3, Adr, Aorta, BFAT, BS,
Pain, Sodium Gabrq, Scn4a, Gabrb1, Cere, Heart, Hypo,
Gabra2, Gabra5, Kidney, Liver, Lung
Gabrb2, Gabrb3,
Scn2a1, Gabra6,
Gabrp
Propranolol 4 Anxiety, Hypertension Adrb2, Adrb3, Htr1b, Adr, Aorta, BFAT, BS,
Adrb1 Kidney, Lung, Mus
Propylthiouracil 2 Agranulocytosis, Anemia, Tpo Liver
Graves' Disease,
Hyperthyroidism, Liver
Pyridostigmine 3 Bche, Ache Adr, BFAT, Kidney
Quinapril 2 Heart Failure, Hypertension Ace Heart, Lung
Rabeprazole 1 Liver, Sodium Atp4a Liver
Ramelteon 1 Liver, Sleep Mtnr1a Liver
Ramipril 2 Blood Pressure, Heart Ace Heart, Lung
Failure, Hypertension, Liver
Rasagiline 3 Parkinson's Disease, Liver, Bcl2, Maob Adr, Aorta, BFAT,
RAS Heart, Kidney, Liver,
Lung, Mus
Regadenoson 0.033 Adenosine, Stress Adora2a Heart, WFAT
Remifentanil 0.016 Pain Oprm1, Oprd1 BS, Lung
Remoxipride 4 Anemia, Mania, MI, MS, Drd4, Sigmar1, Htr2a, Adr, Aorta, BS, Heart,
Schizophrenia Drd3 Hypo, Kidney, Liver,
Lung, WFAT
Repaglinide 1 Liver Abcc8, Pparg Hypo, Kidney, Mus
Riboflavin 1.1 Crystals, Liver Blvrb Adr, BFAT, Kidney
Risedronate 1.5 Fdps Adr, Aorta, BFAT,
Kidney, Liver
Ritodrine 1.7 Adrb2 Adr, Kidney, Lung, Mus
Rituximab 0.8 Infusion, Leukemia C1qa, C1qc, C1qb, Adr, Heart, Kidney,
Ms4a1, Fcgr2b, Fcgr3, Liver, Mus, WFAT
Fcgr4, C1rb
Rivastigmine 1.5 Dementia, Alzheimer's Bche, Ache Adr, BFAT, Kidney
Disease, Parkinson's
Disease, Liver, Nausea and
Vomiting, Vomiting
Rizatriptan 2 Headache, Migraine Htr1b, Htr1d Adr, BS, Lung
Rocuronium 1 Chrna2, Chrm2 BFAT, BS, Heart
Rosiglitazone 3 Diabetes Mellitus, Heart Acsl4, Pparg Adr, Kidney, Liver,
Attack, Liver, Myocardial Lung, Mus
Infarction, Type 2 Diabetes
Rotigotine 5 Depression, Depressive Drd4, Drd3, Adra2b Adr, Hypo, Kidney
Disorder, Parkinson's
Disease, Restless Legs,
Liver, RLS, Restless Legs
Syndrome
Salbutamol 1.6 Infusion, Liver Adrb2, Adrb1 Adr, Kidney, Lung, Mus
Salmeterol 5.5 COPD, Inhalation Adrb2 Adr, Kidney, Lung, Mus
Salsalate 1 Ptgs2, Ptgs1 Aorta, Heart, Kidney,
Lung
Saxagliptin 2.5 BMS, Heart Failure, Type 2 Dpp4 Kidney
Diabetes
Scopolamine 4.5 CP, Liver, Motion Sickness, Chrm3, Chrm2, Chrm4 Adr, BS, Heart, Kidney,
Nausea and Vomiting, Liver, Lung
Vomiting
Selegiline 1.2 Dementia, Depression, Maoa, Maob Adr, Kidney, Liver,
Depressive Disorder, Lung, Mus, WFAT
Parkinson's Disease, Liver
SGS742 4 Gabbr1, Gabbr2 Kidney, Liver
Sibutramine 1.1 Liver, Obesity Slc6a4 Adr, Kidney
Sildenafil 4 Erectile Dysfunction, Pde5a, Pde6g, Pde6h Adr, BFAT, Hypo,
Hypertension, Liver, Kidney
Pulmonary Hypertension
Simvastatin 3 Breastfeeding, Hmgcr Liver
Hypercholesterolemia, Liver,
Pregnancy, Prevention
Spironolactone 0.166 Heart Failure, Hypertension, Cacna1c, Cacna1h, Ar, Adr, Aorta, BFAT, BS,
Liver, Potassium Pgr, Cacna1g, Nr3c1, Cere, Heart, Hypo,
Srd5a1, Cacng1, Kidney, Liver, Lung,
Cacna2d1, Cacna1s, Mus, WFAT
Cacnb1, Cacna1i,
Cacna1d, Nr3c2,
Cacnb3, Cacnb4,
Cacna1b, Cacna1a,
Srd5a2
Stannsoporfin 3.8 Hmox1, Hmox2 Adr, Aorta, Heart,
Kidney
Streptozocin 0.0833 Slc2a2 Kidney, Liver, Mus
Sufentanil 4.416 Clinical Trials Oprm1, Oprd1 BS, Lung
Sulfasalazine 5 Rheumatoid Arthritis, Acat1, Ptgs2, Slc7a11, Adr, Aorta, BS, Heart,
Pregnancy Ptgs1, Pparg, Tbxas1, Hypo, Kidney, Liver,
Chuk, Ikbkb Lung, Mus, WFAT
Sulfinpyrazone 4 Adenosine, Gout Abcc1, Abcc2 BFAT, Heart, Hypo,
Kidney, Liver, Lung
Sumatriptan 2.5 Migraine Htr1b, Htr1d Adr, BS, Lung
Tacrine 2 Alzheimer's Disease Bche, Ache Adr, BFAT, Kidney
Talampanel 3 Gria2, Gria4, Gria1, Adr, Cere, Kidney, Lung
Gria3
Tamoxifen 5 Breast, Breast Cancer, Prkcd, Prkci, Esr1, Adr, Aorta, BFAT, BS,
Cancer, Liver, Menopause Prkce, Prkca, Prkcb, Cere, Heart, Kidney,
Prkcq, Esr2 Liver, Lung, Mus,
WFAT
Tamsulosin 5 Benign Prostatic Adra1d, Adra1a, Adr, BFAT, Heart,
Hyperplasia, BPH, Enlarged Adra1b Kidney, Liver, Lung,
Prostate Mus, WFAT
Tapentadol 4 Chronic Pain, CP, Pain Slc6a4, Oprm1, Oprd1 Adr, BS, Kidney, Lung
Tenecteplase 1.9 Blood Clot, Liver Serpine1, Anxa2, Calr, Adr, Aorta, BFAT, BS,
Canx, Lrp1, Clec3b, Cere, Heart, Hypo,
Plaur, Krt8, Fga Kidney, Liver, Lung,
Mus, WFAT
Teniposide 5 Acute Lymphocytic Top2a Hypo
Leukemia, ALL, Cancer,
Chemotherapy, Leukemia,
Liver
Terbutaline 5.5 Inhalation, Liver, Parenting, Adrb2 Adr, Kidney, Lung, Mus
Pregnancy, Prevention
Terfenadine 3.5 Allergy, Arrhythmia, Liver, Chrm3, Chrm2, Kcnh2, Adr, BS, Heart, Kidney,
Potassium, Rhythm, Chrm4 Liver, Lung, WFAT
Tachycardia
Testosterone 0.166 Consumption, Infusion, Ar Aorta, BFAT, BS,
Liver, Prevention Kidney
Thalidomide 5 Anxiety, Blindness, Cancer, Ptgs2, Fgfr2, Nfkb1 Aorta, BFAT, BS, Cere,
Deafness, Gastritis, Kidney, Liver, Lung,
Immunotherapy, Insomnia, Mus
MS, Multiple Myeloma,
Myeloma, Strabismus
Thiopental 3 Sodium Gabra3, Gria2, Adr, Aorta, BFAT, BS,
Gabra2, Gabra5, Cere, Hypo, Kidney,
Chrna4, Faah, Gabra6 Liver
Thyrotropin Alfa 5 Tshr Adr, Aorta, BFAT,
Kidney, Mus
Tiaprofenic acid 1.5 Cystitis, Liver, NSAID, Ptgs2, Ptgs1 Aorta, Heart, Kidney,
Pain, Plastic Surgery, Renal Lung
Disease
Timolol 2.5 Glaucoma, Hypertension, Adrb2, Adrb1 Adr, Kidney, Lung, Mus
Liver, Myocardial Infarction
Tinzaparin 1.366 Cxcl12, Itga4, Serpinc1 Adr, Aorta, BFAT, BS,
Kidney, Liver, Lung,
Mus, WFAT
Tirofiban 2 Itgb3 Lung
Tizanidine 2.5 ALS, Back Pain, Clinical Adra2b, Adra2a Kidney, WFAT
Trials, Liver Function,
Headache, Hypotension,
Orthostatic Hypotension,
Liver, Migraine, Multiple
Sclerosis, Pain, Sleep
Tofacitinib 3 Rheumatoid Arthritis, Jak2, Jak1 Cere
Clinical Trials, CP,
Prevention, Psoriasis
Tolmetin 2 Rheumatoid Arthritis, Pain Ptgs2, Ptgs1 Aorta, Heart, Kidney,
Lung
Tolterodine 1.9 Urinary Incontinence Chrm3, Chrm2, Chrm4 Adr, BS, Heart, Kidney,
Liver, Lung
Topotecan 2 Cancer, Infusion, Liver, Top1mt, Top1 BFAT, BS, Hypo,
Lung Cancer, Ovarian Kidney, Liver, Lung,
Cancer WFAT
Tositumomab 0.8 Cancer, Chemotherapy C1qa, C1qc, C1qb, Adr, Heart, Kidney,
Ms4a1, Fcgr2b, Fcgr3, Liver, Mus, WFAT
Fcgr4, C1rb
Tranylcypromine 1.5 Anxiety, Anxiety Disorder, Maoa, Maob Adr, Kidney, Liver,
Depression, Liver Lung, Mus, WFAT
Travoprost 0.75 Glaucoma, Hypertension Ptgfr Heart, Lung, Mus
Trazodone 1 Depression, Sleep Slc6a4, Adra1a, Htr2a, Adr, BFAT, BS, Cere,
Htr2c, Adra2a Heart, Kidney, Lung,
Mus, WFAT
Treprostinil 2 Hypertension, Infusion, Ppard Adr, Kidney, Liver
Inhalation, Liver
Tretinoin 0.5 Acne, Leukemia Rxrb, Aldh1a1, Aorta, BFAT, BS,
Aldh1a2, Rxrg, Rarg, Heart, Kidney, Liver,
Gprc5a Lung, Mus
Triamcinolone 1.466 Inhalation, Liver Nr3c1 BFAT, Cere, Mus
Triamterene 4.25 Edema, Hypertension, Scnn1a, Scnn1g, Adr, Aorta, BFAT,
Potassium Scnn1b Kidney, Liver, Lung
Triazolam 1.5 Insomnia, Liver Gabra3, Gabrg3, Adr, Aorta, BFAT, BS,
Gabrq, Gabrb1, Tspo, Cere, Heart, Hypo,
Gabra2, Gabrr2, Kidney, Liver, Lung,
Gabra5, Gabrb2, Mus, WFAT
Gabrb3, Gabra6,
Gabrp, Gabrr1
Trifluridine 0.2 Cancer, CF, Herpes, herpes Tyms Aorta
simplex virus, Keratitis
Trihexyphenidyl 3.3 Chrm3, Chrm2, Chrm4 Adr, BS, Heart, Kidney,
Liver, Lung
Tubocurarine 1 Chloride Chrna2, Ache BFAT, Kidney
Urokinase 0.2 Cancer, Nursing Serpine1, Nid1, Plat, Adr, BFAT, Heart,
Plaur, Plau, Lrp2, Hypo, Kidney, Liver,
Serpina5, St14 Lung, Mus, WFAT
Valsartan 1 Blood Pressure, CHF, Heart Agtr1a Adr, Heart, Kidney,
Failure, Hypertension, MI, Liver, Mus
Myocardial Infarction
Vapreotide 0.5 Tacr1 BS
Vardenafil 4 Erectile Dysfunction Pde5a, Pde6g, Pde6h Adr, BFAT, Hypo,
Kidney
Vasopressin 0.166 Blood Pressure, Stress, WS Avpr1a, Avpr2 BFAT, Kidney, Liver,
Lung
Vecuronium 0.85 Chrna2 BFAT
Velaglucerase alfa 0.1833 Gaucher Disease, Infusion Gba Lung
Venlafaxine 5 Anxiety, Anxiety Disorder, Slc6a4 Adr, Kidney
Blood Pressure,
Constipation, CP,
Depression, Depressive
Disorder, Dry Mouth, EA,
GAD, Headache, Insomnia,
Liver, Panic Disorder
Verapamil 2.8 Arrhythmia, Cluster Cacna1c, Slc6a4, Adr, Aorta, BFAT, BS,
Headaches, Headache, Cacna1g, Cacna1s, Cere, Heart, Hypo,
Hypertension, Liver, Cacnb1, Kcnj11, Kidney, Lung, WFAT
Migraine Cacna1i, Cacna1d,
Cacnb3, Cacnb4,
Kcnh2, Scn5a,
Cacna1b, Cacna1a
Vildagliptin 1.5 Diabetes Mellitus, Dpp4 Kidney
Hyperglycemia,
Hypoglycemia, Type 2
Diabetes
Vincristine 5 Cancer, Chemotherapy, Tuba4a, Tubb5 BFAT, Cere, Hypo,
Liver, PFS Kidney, Liver, WFAT
Vitamin A 1.9 Dhrs3, Retsat, Adr, Aorta, BFAT, BS,
Aldh1a3, Rdh13, Cere, Heart, Hypo,
Aldh1a1, Rbp1, Kidney, Liver, Lung,
Aldh1a2, Rdh5, Lrat, Mus, WFAT
Rdh11, Rdh14, Rdh8,
Dhrs4
Vorinostat 2 Liver Hdac1, Hdac3, Hdac8, Adr, Aorta, BFAT, BS,
Hdac6, Hdac2 Heart, Hypo, Kidney,
Liver, Lung
Warfarin 1 Blood Clots, CP, Prevention Vkorc1 Adr, BFAT
Yohimbine 0.6 Type 2 Diabetes Htr1b, Kcnj8, Kcnj11, Adr, BFAT, BS, Cere,
Kcnj12, Htr2a, Htr2c, Heart, Hypo, Kidney,
Drd3, Adra2b, Kcnj1, Lung, Mus, WFAT
Htr1d, Adra2a
Zaleplon 1 Insomnia, Sleep Tspo BFAT, Lung
Zanamivir 2.5 Influenza, Inhalation, Neu2 BFAT, Kidney, Liver,
Prevention Lung
Zidovudine 1.1 HIV, Liver Tert Lung
Zolmitriptan 3 Headache, Liver, Migraine Htr1b, Htr1d Adr, BS, Lung
Zolpidem 2.6 Cancer, Insomnia, Liver, Gabra3, Gabra2 Adr, Aorta, BFAT, BS,
Prevention, Seizure, Sleep Cere, Hypo, Kidney
Zopiclone 5 Addiction, Depression, Gabra3, Tspo, Gabra2, Adr, Aorta, BFAT, BS,
Insomnia, Liver, Liver Gabra5 Cere, Hypo, Kidney,
Enzymes, Pill, Sleep Lung
Data regarding circadian oscillations, including coding and non-coding genes, are available via the World Wide Web (www) bioinf.itmat.upenn.edu/circa, a subset of which is summarized in Table 2, infra.
TABLE 2
Circadian Oscillations in Transcript Expression Data
(numbers represent circadian time in hours)
Brown Brain- Cere- Hypo- White
Target Gene Adrenal Aorta Fat stem bellum Heart thalamus Kidney Liver Lung Muscle Fat
AAAS 6
AACS 8
AADAC 21 22
AAED1 9.5
AAGAB 6 8
AAK1 17
AAMP 0
AASDH 21
AASDHPPT 4.5
AASS 21.5 21
AB041803 6.5
ABAT 21 11.5
ABCA1 1.5
ABCA12 22
ABCA13 7
ABCA17 11.5
ABCA2 22
ABCA3 16 19
ABCA4 21
ABCA5 23
ABCA6 22
ABCA7 2
ABCA8 6
ABCA8A 21 22
ABCA9 23
ABCB1 5
ABCB10 8
ABCB11 0 12
ABCB4 21.5
ABCB6 9
ABCB7 9.5 10
ABCB8 12
ABCC1 19 21 22
ABCC10 8
ABCC2 23
ABCC4 7 7 8 6
ABCC5 11 8.5
ABCC9 2
ABCD1 8
ABCD2 5
ABCD4 23
ABCE1 0
ABCF1 6
ABCF2 10 11 11
ABCF3 20
ABCG1 18
ABCG2 20.5 19.5
ABCG4 21 19
ABCG5 20
ABCG8 1.5
ABHD11 19 22 0.5
ABHD14A 22 20.5
ABHD14B 5.5 5 5 7
ABHD15 0.5
ABHD16A 20
ABHD2 23 7
ABHD3 7 7
ABHD4 14.5 12 13
ABHD6 23 0 23 23
ABHD8 18.5 18
ABI1 23 23
ABI2 13 8
ABI3 23
ABL1 23
ABLIM1 22
ABLIM2 21
ABLIM3 21
ABP1 23 4
ABR 20.5
ABRA 6
ABRACL 3
ABTB1 5
ABTB2 9
AC027184.1 21
AC083948.1 21 21 18
AC091683.2 21
AC101527.1 21
AC109305.2 20
AC122012.1 20
AC122260.2 14
AC122872.1 2
AC130208.1 15
AC132253.3 23.5 12.5
AC132457.1 19
AC133509.2 19
AC139157.1 21 18
AC141881.34 23 9.5 10
AC150897.1 22
AC153928.2 19 1
AC158295.1 20
AC159129.1 15.5
AC168120.1 6
AC174597.1 1
AC225448.1 21 18.5 17
ACAA1 21.5
ACAA2 21.5
ACACA 2
ACACB 18 19.5
ACAD10 20 23 22.5 0
ACAD11 8 2.5
ACAD8 19
ACADL 9
ACADM 1.5
ACADVL 18.5 21 22 23 20.5 8
ACAN 21 22
ACAP2 22 16
ACAP3 22 22 2
ACAT2 0
ACAT3 21
ACBD4 22
ACBD5 6 23 22.5
ACCS 22.5 16 5 6
ACE 22.5
ACER2 10
ACHE 5.5
ACIN1 16.5 18 19.5 18 16 1
ACLY 19
ACMSD 13
ACN9 10
ACO2 1 3
ACOT1 2 13
ACOT11 4
ACOT12 20
ACOT2 6 20.5
ACOT4 5.5 19.5 1
ACOT9 22.5 23
ACOX1 23
ACOX2 5
ACOX3 23
ACOXL 22 15
ACP2 21
ACP6 22
ACPP 5.5
ACSF3 20.5
ACSL1 14 13
ACSL3 20 21
ACSL4 21
ACSL5 0 23.5
ACSM5 22 23 17
ACSS2 5.5
ACSS3 17
ACT1 8
ACT2 23
ACTA2 8
ACTB 12
ACTN1 22
ACTN4 2
ACTR1B 22
ACTR3 11.5
ACTR3B 23 22 19 20 21
ACVR1 7.5 10 11.5
ACVR1B 19
ACVR1C 15 8
ACVR2A 22
ACVR2B 23
ACY1 22 23 21
ACY3 15.5 17 18 15
ACYP1 22.5
ADAL 22
ADAM10 22.5
ADAM12 22
ADAM17 21 21
ADAM19 18 21 22
ADAM22 0.5 22.5
ADAM23 22
ADAM28 20
ADAM29 8
ADAM32 7
ADAM6B 0 5 0 0 0
ADAM9 8
ADAMDEC1 12 12
ADAMTS1 18.5
ADAMTS10 21
ADAMTS12 10 9
ADAMTS15 1.5
ADAMTS16 12 8
ADAMTS17 0
ADAMTS2 0
ADAMTS3 10.5
ADAMTS4 6
ADAMTS5 2.5
ADAMTS6 21 21
ADAMTS8 10 9.5
ADAMTS9 22
ADAMTSL1 20 18
ADAMTSL3 4
ADAMTSL4 22
ADAMTSL5 16.5 13
ADAP1 17
ADAP2 9
ADAR 2 5
ADARB1 20.5
ADAT1 22 22.5 23
ADAT2 0.5
ADC 10 11
ADCK2 18.5
ADCK3 11
ADCK4 21 22 9
ADCK5 1 4
ADCY3 13
ADCY4 20.5
ADCY5 21
ADCY6 12
ADCY7 0.5
ADCY8 12
ADCY9 9
ADCYAP1R1 8.5
ADD3 18
ADH1C 21 13
ADH4 11.5
ADH6-PS1 22 22
ADH7 9 2
ADHFE1 12.5 10
ADI1 10
ADIPOQ 14 13 14.5 13 18
ADIPOR2 5
ADM 21
ADNP2 22.5 2 20.5
ADO 6 11 10
ADORA1 12
ADORA2A 7
ADORA2B 19
ADPGK 18 17 17
ADPRHL1 20.5 19 22 16
ADPRHL2 9 9
ADRA1A 8 10 6 5
ADRA1B 22 22 21 22 22 21.5
ADRA1D 22
ADRA2B 9
ADRB1 19
ADRB2 8
ADRB3 12
ADRBK2 0 3
ADRM1 16
ADSS 20 21
ADTRP 22 22
AEBP1 12
AFAP1 9
AFAP1L2 1.5 3 7 14 2
AFF1 9 9
AFF2 7
AFF3 5.5
AFF4 23
AFG3L2 0
AFMID 1
AFTPH 4
AGA 21 19.5
AGAP1 19 16
AGAP2 5 8 7.5 10 6
AGAP3 19
AGBL5 19 22.5
AGFG1 13 15 13 16 14 12.5
AGFG2 20 0 17
AGL 3
AGMAT 6
AGMO 22 8.5
AGPAT1 4
AGPAT2 15
AGPAT3 2
AGPAT4 12
AGPAT5 22.5
AGPAT6 6
AGPAT9 0.5 23 2 23
AGPHD1 23 8
AGPS 21.5
AGTPBP1 23
AGTR1 3
AGXT 17
AGXT2L1 21
AHCTF1 5
AHCYL2 12 13
AHDC1 17
AHK 19 1
AHK2 13.5
AHSA1 7 7 8.5
AHSA2 6.5
AI182371 14 8 13
AI317395 22
AI606181 22
AI607873 5
AIF1L 23
AIFM1 6 15
AIFM2 16
AIG1 16
AIMP1 22
AIRN 8
AK1 17
AK2 17
AK3 14 14 15 17 14 13 12.5 13 13 14
AK4 21.5 2.5
AK5 2 6
AK8 7
AKAP1 21.5
AKAP11 23
AKAP12 18 21
AKAP13 22.5
AKAP17B 22
AKAP5 18 14.5 15
AKAP9 1 10.5 9
AKIP1 20 21
AKIRIN2 21
AKR1B10 21 22
AKR1B7 5.5
AKR1C1 23 22 6
AKR1C14 1
AKR1C19 6.5 7 7 5
AKR1C20 10
AKR1D1 4 2
AKR1E2 14.5
AKT1 22.5
AKT2 5 9 9.5 9 2
AKT3 23
AKTIP 21
AL731554.1 15
AL807771.1 19 23
ALAD 2
ALAD2 7.5
ALAS1 6
ALCAM 23.5
ALDH18A1 20
ALDH1A1 22 6 23 6
ALDH1A2 22
ALDH1A7 13
ALDH3A1 4 5 8 6 3 5
ALDH3A2 10
ALDH3B1 21
ALDH3B2 0
ALDH7A1 7 22
ALDH8A1 8
ALDH9A1 5
ALDOA 20 16
ALDOB 12
ALDOC 19.5
ALG11 15
ALG12 8
ALG14 2.5 23
ALG3 11 8.5
ALG5 23
ALG6 2 23
ALG8 1 1 1 23 2.5
ALKBH3 16
ALKBH6 16.5
ALKBH7 1
ALKBH8 0.5
ALMS1 6 8.5 6 7
ALOXE3 23 22
ALPK1 6
ALPK2 20
ALPL 7
ALS2 6
ALS2CL 15
ALS2CR12 16 20.5 17 20 16 14.5 15 18
ALYREF 5.5 9
ALYREF2 13
AMACR 20
AMDHD1 5 6
AMDHD2 23 14
AMFR 4.5
AMIGO2 4.5
AMMECR1 7
AMOT 5.167
AMOTL1 5.833
AMOTL2 3.167
AMPH 13
AMT 3.167
ANGEL1 4.833
ANGEL2 6
ANGPT1 5
ANGPT2 14.5 0.5 2.833
ANGPTL1 12
ANGPTL2 10
ANGPTL4 1
ANGPTL7 23 23
ANK1 8 9 21 13.5
ANK2 3 3
ANK3 23
ANKH 21
ANKLE2 15
ANKMY2 12 15 20 13 0
ANKRA2 22
ANKRD11 5.5
ANKRD12 10.5 10 3
ANKRD13A 6
ANKRD13C 6
ANKRD16 8
ANKRD17 8 22
ANKRD23 22.5 20 17 23
ANKRD28 6.5 7
ANKRD33B 12
ANKRD34C 0.833
ANKRD40 21
ANKRD44 22.5
ANKRD46 14
ANKRD49 11 11
ANKRD5 20 17 21
ANKRD50 22 2 2
ANKRD52 11 22
ANKRD9 0.5 2
ANKS1A 20 19
ANKUB1 20 22 3
ANLN 22
ANO3 17
ANO4 8
ANO6 16.5
ANO8 5 1
ANP32A 12 21 13 11.5
ANP32-PS 15 14
ANPEP 18 19.5 17
ANTXR1 0 21 22.5
ANTXR2 22
ANXA11 6.5 7 9
ANXA2 6.5
ANXA3 21.5 19
ANXA5 3.5 23 0
ANXA7 20 19
ANXA8 7
ANXA9 21 22
AOC3 6 9
AP1AR 22 20 23 20
AP1G1 11 12.5 13 12 12 12 12 12 12 12 11 14
AP1M1 5
AP1S1 4.167 21.5
AP1S2 21
AP2A1 12
AP2A2 17
AP2S1 21.5
AP3D1 19
AP3M1 11
AP5S1 9
APAF1 8 10
APBA3 23.5 21
APBB1IP 11
APBB3 22
APC 9.5
APC1 7.5
APC10 10
APC11 12
APC13 18
APC16 23
APC7 9.5 11
APCDD1 6
APEX1 5.5 17 13
APEX2 10
APH1B 8
APH1C 8
API5 22
APIP 4
APLN 8
APLNR 21
APOA1BP 15
APOA5 19.5
APOBEC1 22
APOBEC2 5.5
APOC1 14.5
APOC2 7
APOC3 22 20 20
APOD 12 14
APOE 1
APOL6 9
APOLD1 19
APON 21.5 21.5 19.5 5.5
APPL1 22 0
APPL2 8 8 6.5
APRT 12 10.5 9
AQP1 6.5
AQP11 9.5
AQP3 5.5
AQP4 5 7 20
AQP6 0
AQP7 2.5
AQP8 18.5 18
AQP9 18 23.5 21 18 19
AQR 0 19 17
AR 7 7 3
ARAF 5
ARAP1 8.5 6 6
ARAP2 7 9
ARAP3 15 15 15 17 14 14 14.5
ARF1 18.5
ARF3 22 20 23
ARF5 23
ARFGAP1 23 21
ARFGEF1 21 17
ARFGEF2 11
ARFIP1 3.5
ARFIP2 23.5
ARGLU1 10 11 10
ARHGAP1 23
ARHGAP10 8.5 8 9 9
ARHGAP12 4
ARHGAP17 0
ARHGAP18 23
ARHGAP20 18 23.5
ARHGAP21 16
ARHGAP23 4
ARHGAP24 2.5 4
ARHGAP25 23 21 0
ARHGAP26 21.5
ARHGAP27 18 11
ARHGAP29 0
ARHGAP30 21 3.5 20.5 18.5 0
ARHGAP31 20
ARHGAP35 22
ARHGAP39 8
ARHGAP5 9 9 14 11
ARHGDIB 8 5.167
ARHGEF1 11
ARHGEF10L 5
ARHGEF12 0
ARHGEF15 9
ARHGEF17 11
ARHGEF18 8.5 5.167
ARHGEF19 1 22.5
ARHGEF26 5.5 7 17
ARHGEF3 6
ARHGEF37 0.5
ARHGEF5 8 9 4 9.5
ARHGEF7 22
ARHGEF9 12
ARID1A 20
ARID1B 16
ARID5B 19
ARIH1 15
ARIH2 22
ARL10 17 22
ARL15 16
ARL2BP 19
ARL3 18
ARL4A 12
ARL4D 22 23 13.5
ARL5B 23
ARL6IP1 15
ARL6IP5 15 13.5 14 13
ARL8A 11 15 12 12
ARL8B 4
ARMC2 23 21.5
ARMC9 22
ARMCX1 22 20 19 18.5
ARMCX3 2
ARMCX4 8
ARNT 18
ARNTL 19
ARPC1A 1
ARPP19 21 19 16 15.5 17
ARRB1 20
ARRDC2 9
ARRDC3 23
ARRDC4 23.5 22 22 23
ARSA 17 23
ARSB 21
ARSG 23 6 21 22
ARSJ 23 20 23
ARSK 20
ART1 9
ART3 14.5
ART4 15
ARVCF 12
AS3MT 16
ASAH1 21.5
ASAP1 22
ASAP2 0 21
ASAP3 23 16
ASB10 21
ASB12 21
ASB13 10.5
ASB18 3.5 7 15.5
ASB2 14 14
ASB4 23
ASB9 11
ASCC3 7 6 4.5
ASF1A 12 9
ASIC5 21
ASL 0 6
ASNS 18.5
ASPA 4 6 9
ASPDH 23
ASPG 20 20 22
ASPH 2
ASPSCR1 7.5
ASTE1 8 12 22
ASTN2 23
ASXL3 20
ATAD1 2
ATAD2 9
ATAD2B 7
ATAD3A 1.5 23 21 3
ATAD5 22
ATAT1 6
ATF2 17
ATF5 11 12 12.5 11 9 11.5 10 13 15 12 10.5 14.5
ATF6 22.5
ATF7IP 17
ATG16L1 0 0 0 1 0
ATG16L2 11
ATG2A 21.5 23
ATG3 19
ATG7 19
ATHL1 2
ATIC 15
ATL1 9 15 15.5 12 14 12 15.5
ATMIN 13
ATOX1 2 0 0 16.5 0
ATP10A 22
ATP10B 14.5 14.5 16 15 14 14 14 15 15 13 16.5 16
ATP10D 17 14
ATP11A 10
ATP11C 9 10 9.5
ATP13A3 6 6
ATP13A4 20.5 10
ATP1A1 19.5 21 23
ATP1A2 12 8.5
ATP1B1 5.5
ATP1B2 1
ATP1B3 6
ATP2A3 21
ATP2B1 7
ATP2B2 21 22
ATP2B4 19
ATP2C1 14 13 15 15
ATP4A 23
ATP5A1 22
ATP5D 9 10 18.5 4
ATP5I 19 22
ATP5J 18
ATP5J2-PTCD1 23
ATP5O 6.5
ATP5S 8
ATP5SL 22.5
ATP6AP1 22
ATP6V0A1 10.5
ATP6V0A2 16
ATP6V0A4 19.5 12
ATP6V0B 3
ATP6V1B1 22
ATP6V1B2 2
ATP6V1C1 12 11
ATP6V1C2 3
ATP6V1D 2 2 23.5 22
ATP6V1F 17
ATP6V1G3 7.5
ATP6V1H 23
ATP7B 2
ATP8A1 1.5 5.5 1.5 23
ATP8A2 6.5
ATP8B1 8.5 12 12 13
ATP9A 8
ATPBD4 11.5
ATPIF1 6
ATRNL1 22
ATXN1 23
ATXN2 10 12.5
ATXN2L 8 11
ATXN3 22
ATXN7 7
ATXN7L1 21
ATXN7L3B 21 19
AUH 11 13 15
AUTS2 13 12
AVEN 6 2.5
AVL9 17 23.5
AVPI1 19
AVPR1A 7 9 15 10
AVPR2 20 19 19 21
AW551984 21.5
AXIN2 16 11 0
AXL 21 23
AZIN1 1.5
B230307C23RIK 21 21 22
B230314M03RIK 19
B330016D10RIK 17 16
B3GALNT2 22 21
B3GALT1 11
B3GALT2 23
B3GALTL 3
B3GAT3 22 23.5
B3GNT8 16.5 16
B3GNT9 17
B430212C06RIK 17 17 19
B430219N15RIK 11.5 11 2
B4GALNT1 23.5 5 1 3 1.5
B4GALNT3 13
B4GALT1 23 0
B4GALT2 0
B4GALT5 21 14
B4GALT6 8.5
B4GALT7 4.5 21
B530045E10RIK 9 11
B9D2 14
BAAT 6 7 6 11 5 10
BABAM1 4
BACE1 11 15
BACH1 23
BACH2 0
BAG3 0
BAG4 18 15 14
BAG6 9
BAI2 13
BAIAP2 21 22.5
BAIAP2L1 2.167
BANF1 10.5 11.5 12 10 11 11
BANK1 11 12 14 11
BANP 11 15
BARD1 6
BASP1 23
BATF2 10
BAZ1A 6
BAZ1B 6 9
BAZ2A 13 17
BBOX1 13 13.5 12
BBS12 8 22
BBS2 23
BBS4 21 7
BBS7 7
BBS9 15
BC005561 17 18 13 17 13.5 18
BC018242 9.5 19
BC021614 21
BC021785 11.5
BC023105 7
BC025920 9 0 3
BC026585 0.5
BC029722 2.5
BC030307 11
BC030500 23
BC048679 0 2 22 22 2.5
BC051142 1.5
BC067074 5.5
BCAN 22
BCAP29 11
BCAR1 9.5
BCAR3 14.5 14.5 17 13 13
BCAS3 3
BCAT1 21
BCHE 2.5
BCKDHA 22.5
BCKDHB 5 3 6 13
BCKDK 22
BCL2 3
BCL2L1 22
BCL2L10 10.5 8
BCL6B 9
BCL7A 23
BCL7C 23
BCL9L 6 8 10 8.5 7 5 9 9 9
BCO2 19.5
BCORL1 21.5
BCR 23
BCS1L 18
BDH1 23
BDKRB1 22 23 0
BDNF 4.5
BECN1 12.5 10 10
BEGAIN 0 0.5
BEND5 12 13 13 13 15 14 14 14 13 15 14
BEND6 5 10
BET1 9 7 10 8
BET1L 20.5
BEX1 22 16
BEX6 12 11
BFAR 20
BFSP1 0.5 23
BHLHB9 13
BHLHE40 20 2 19
BHLHE41 0
BHMT2 15.5
BICC1 19.5 21
BICD2 13 18
BIK 15
BIRC3 19.5 19.5 20.5 21 21.5 21 19 18
BLCAP 23.5
BLOC1S3 21
BLVRB 10
BMF 8
BMP1 22.5
BMP2 11
BMP2K 4.167
BMP3 7 11
BMP4 14
BMP5 8.5
BMP6 1
BMPR1A 4 22.5 7
BMPR1B 15 13
BMYC 7
BNC2 23
BNIP3 16
BOK 11.5
BOLA1 9 10 12
BPHL 15 15
BPIFB5 11.5
BPNT1 7
BPTF 2
BRAF 10
BRAP 21 23
BRCA2 14.5 16 15
BRD1 11
BRD2 22 8.5
BRD7 6 3
BRF2 23
BRI3 0
BRI3BP 11 0
BRIP1 12
BRK1 22
BRMS1L 20.5 22
BRP44L 23 22.5
BRSK2 23
BRWD3 8
BSCL2 8 23
BSDC1 22 23 21
BSPRY 22
BST2 23
BTBD11 23.5
BTBD3 8 11 10
BTBD6 22
BTBD9 1
BTD 12 21 10.5
BTF3 21
BTF3L4 21.5
BTG1 22
BTNL9 10.5
BZW1 5 1
BZW2 8 7 7.5
C10ORF107 4 6 2
C10ORF11 22 21
C10ORF140 2.5
C10ORF2 16
C10ORF27 20
C10ORF46 19
C10ORF47 8
C10ORF71 0
C10ORF90 14.5
C11ORF1 9 9.5 10
C11ORF24 11
C11ORF31 6.5
C11ORF41 9
C11ORF46 8
C11ORF51 22
C11ORF52 22 1
C11ORF53 21
C11ORF54 4 10 17 5
C11ORF65 8.5
C11ORF71 22
C11ORF73 23 22.5
C11ORF83 20.5 2
C11ORF86 6 6
C11ORF87 13
C11ORF96 2
C12ORF10 12
C12ORF23 0
C12ORF29 7 7
C12ORF34 21
C12ORF35 21.5
C12ORF4 7
C12ORF44 19 22 13 13.5
C12ORF45 11
C12ORF49 5.167
C12ORF5 13
C12ORF56 11.5
C12ORF65 19.5 22
C12ORF68 3
C12ORF69 0 3 6
C14ORF101 9
C14ORF118 21
C14ORF126 1
C14ORF129 10
C14ORF135 0 8 23.5
C14ORF149 8 10
C14ORF159 10
C14ORF45 23
C14ORF49 18 16
C14ORF79 7 1
C14ORF93 13 21.5
C15ORF24 23.5
C15ORF39 10 10 10 17
C15ORF40 8
C15ORF41 16 17
C15ORF52 8 22 22.5
C15ORF58 23 22
C15ORF61 21
C16ORF5 22
C16ORF62 12 8
C16ORF70 7
C16ORF72 13
C16ORF73 16 13 13 13 14 15.5 15
C16ORF80 8 10.5 2
C16ORF87 22 21
C16ORF88 13
C16ORF89 22
C16ORF96 19
C17ORF101 21
C17ORF103 1.5
C17ORF109 22 10 16 17 14.5 9
C17ORF39 22
C17ORF53 2
C17ORF63 5 8
C17ORF70 6
C17ORF78 20 21
C18ORF1 23
C18ORF32 23 3.5
C18ORF8 4.5
C19ORF12 13 17 16 20 19
C19ORF40 7
C19ORF42 7 6
C19ORF43 2 3 4.5 2 3 0 3.5 4 5
C19ORF44 23
C19ORF46 22
C19ORF6 19
C19ORF60 10.5
C19ORF66 19.5
C19ORF69 18
C1GALT1 11
C1GALT1C1 3 5 5
C1ORF100 18 20.5 19 23
C1ORF106 20
C1ORF110 21
C1ORF115 19
C1ORF116 10.5 0
C1ORF123 17 0 22
C1ORF127 12 15
C1ORF131 23
C1ORF168 11.5 13 11
C1ORF172 17 6 11
C1ORF192 9.5
C1ORF198 9.5 15
C1ORF21 23 1.5
C1ORF210 6.5 12.5
C1ORF228 4.5
C1ORF31 14 20.5 17 5.5
C1ORF38 8.5
C1ORF50 8
C1ORF51 22.5 0
C1ORF86 23
C1ORF87 19.5
C1QL3 13 15 14
C1QTNF1 9
C1QTNF2 16
C1QTNF3 11.5 14.5
C1QTNF9 7
C20ORF173 22 22
C20ORF194 7
C20ORF24 1
C20ORF3 6 9 10 14
C20ORF43 21 13 17
C20ORF72 22 23
C20ORF94 0
C20ORF96 9.5
C21ORF7 14 9
C21ORF91 5 22
C22ORF13 15
C22ORF25 3.167
C22ORF39 18
C22ORF40 22.5
C230004F18RIK 9 9.5 9 9.5 9.5 9 8 10 8.5 9
C2CD2 4
C2CD2L 18.5 23.5 19 22
C2CD3 11 12 12 11 13 13 11 12 12 10.5 12
C2ORF28 22
C2ORF43 22
C2ORF44 7 9
C2ORF54 12 0 23
C2ORF68 18.5 20 22 18.5
C2ORF74 5.5 22 21
C2ORF80 7
C3 0
C330021F23RIK 20
C3ORF14 19 11
C3ORF18 11
C3ORF23 5
C3ORF33 6
C3ORF37 21.5
C3ORF38 5 3.5
C3ORF58 16 19
C3ORF67 4.5
C3ORF80 13.5 5.5
C4B 19
C4ORF21 19
C4ORF32 6 15
C4ORF33 22 22
C4ORF34 13 8
C5 0
C530005A16RIK 9 13
C5AR1 9
C5ORF15 22 9
C5ORF34 0
C5ORF44 21 5
C5ORF45 10 10 12
C5ORF51 1
C5ORF62 16
C5ORF63 9
C5ORF65 11
C6 21
C6ORF106 17
C6ORF108 20.5 23 0 20
C6ORF118 20 23
C6ORF170 5 7.5 7
C6ORF211 3.5
C6ORF222 10 9.5
C6ORF47 7.5
C6ORF62 21
C6ORF70 23
C6ORF89 23
C7ORF26 19
C7ORF31 0
C7ORF45 11.5
C7ORF49 17 11
C7ORF53 9 12
C7ORF57 22
C7ORF58 7
C7ORF59 8 9 7
C7ORF60 6.5
C7ORF63 7 11
C7ORF70 6 8
C8A 23 20
C8G 8.5
C8ORF34 10
C8ORF4 9 8 12
C8ORF40 10.5 19
C8ORF42 2
C8ORF83 8
C8ORF84 22.5
C8ORF85 1 13
C9ORF102 8
C9ORF114 10
C9ORF123 5.167
C9ORF142 23
C9ORF16 22 23
C9ORF167 22 20 23
C9ORF174 22
C9ORF40 8.5
C9ORF46 18.5
C9ORF85 6 6
C9ORF86 23 0
C9ORF89 10
C9ORF93 23.5 23.5
CA11 8.5 14 21
CA12 7
CA13 14
CA14 23 12
CA2 12
CA3 2
CA4 17 22
CA5B 22
CA8 11
CAAA01083517.1 11
CAAA01083517.2 23
CAB39 2
CABIN1 11
CABLES1 10
CAC1C 23.5
CAC1D 22
CAC1H 18
CACHD1 23
CACNB2 23
CACNB3 10 16 22 10 10
CACNB4 18
CACNG4 3
CACNG5 22 1.5
CACNG8 3.833
CACYBP 13
CAD 11 14 21 16
CAD 22 12
CADM4 22 8
CALB1 22
CALB2 9
CALCOCO1 20 12
CALCRL 22 4 5 23 22.5 0.5 1
CALD1 23
CALM1 23
CALM2 21
CALML5 22
CALN1 20.5 20 11
CALR 11.5 7 5.5
CALU 23 22
CAMK1D 7.5
CAMK2B 12
CAMK2D 14
CAMK2G 17 19 19.5
CAMK2N1 13
CAMKK1 10 13.5
CAMKK2 13 11.5 11 8
CAMKMT 10.5
CAMSAP1 23.5
CAMSAP3 17
CAMTA1 4
CAMTA2 13 13
CAND1 20
CAND2 19
CANX 16
CAP1 18.5 3
CAPN2 11 11 14.5
CAPN5 3
CAPNS1 8 12
CAPRIN1 12
CAPRIN2 12 13
CAPZA2 22
CAPZB 6 8
CARD10 22.5
CARHSP1 23 19
CARHSP1 8 6
CARNS1 0 0
CARS 9
CARS2 1 7.5
CASC4 15 13 13 14 13
CASD1 5.5
CASP2 17 20 14 18
CASP6 7
CASP8 21
CASQ2 11
CASS4 19 21
CAT 22 13.5 2.5 21
CATSPER2 0
CATSPER3 18 22 22.5 20.5 16 17 15
CAV1 6.5 9 10 6
CAV2 12
CBFA2T3 22
CBL 6
CBLB 23
CBLC 4 13
CBR1 22 22.5 19.5
CBR2 4.5
CBS 21 19.5
CBX1 6
CBX4 22
CBX5 9
CBX7 19 19
CC1 2 21
CC2D1B 10
CC2D2A 0
CCAR1 18
CCBE1 19
CCBL1 13 22
CCBP2 22 21
CCDC102A 21.5
CCDC108 20 4
CCDC112 9
CCDC126 10.5
CCDC129 21 23.5
CCDC134 21
CCDC135 18
CCDC138 8
CCDC141 13 13 14 16 14 12 12 13 11.5 13
CCDC153 8
CCDC159 12
CCDC162 15 15
CCDC163 6
CCDC166 2 3.5
CCDC17 9 6
CCDC28A 19
CCDC3 8
CCDC30 4
CCDC39 18 19 21 22 23 18 19 17 20.5
CCDC41 13
CCDC50 20 23.5 0
CCDC57 15 19 14 23 11
CCDC6 17
CCDC60 12
CCDC64 10.5 11
CCDC66 10.5 13
CCDC69 0
CCDC74A 22 4
CCDC75 5
CCDC77 1
CCDC8 20
CCDC80 10.5 12.5 15
CCDC84 10
CCDC85A 23
CCDC88C 23 22
CCDC91 10
CCDC92 5
CCKAR 9 1
CCKBR 4.5
CCL11 3
CCL17 22.5
CCL20 9.5 8
CCL25 12
CCNC 22
CCND1 22 9
CCND3 22
CCNE1 2 6.5
CCNF 4 4 7 5 4 3 2
CCNG1 0 13 16
CCNG2 2.5 5
CCNH 23.5 0.5 23 19
CCNJL 8.5
CCNL2 13 22
CCNT2 8 11 13 17 19 10
CCNY 19
CCR5 23 23
CCR7 21 18 7.5
CCRL1 14
CCRL2 10
CCRN4L 20 21
CCS 13 12
CCT2 11.5
CCT3 7
CCT5 14
CCT7 17
CD14 17
CD151 9
CD163 19.5
CD164 23.5 23.5
CD164L2 3.5 22
CD180 18.5
CD19 6.5
CD200 23
CD200R1 19.5
CD200R1L 21.5 22
CD209D 5
CD244 10.5 8
CD274 23
CD28 21 22.5 21.5
CD2AP 17
CD300A 22.5 19
CD300LG 17
CD302 19.5
CD33 15 17 10 16 15 9.5 17
CD34 19 20 0
CD36 23.5
CD37 1.5 0
CD38 23 23 1 23
CD4 21
CD40 21.5
CD44 20 19
CD47 23 7 0
CD52 16 19 14
CD59 3
CD59A 8
CD68 19
CD69 9 12 2 13
CD74 21 22.5 5 23
CD79A 1.5
CD79B 22
CD81 22
CD82 8
CD8A 13
CD8B 5.5
CD93 20
CD97 22 23 22
CDA 13 11
CDADC1 22
CDAN1 22
CDC14A 20.5
CDC14B 8.5
CDC25A 0 0
CDC25B 1
CDC27 22
CDC34 3
CDC40 20 21
CDC42 9
CDC42BPA 22 23
CDC42BPB 0
CDC42EP3 19
CDC42EP4 23
CDC42EP5 23.5 0 1 1 1
CDC42SE1 5.5
CDC5L 16.5 13
CDC73 21.5 5
CDCA7L 5
CDCP1 22 17
CDH1 10 9
CDH11 10
CDH13 20 23
CDH19 1.167
CDH2 22
CDH20 23
CDH22 10 9
CDH3 7 4
CDH4 22
CDH5 22.5
CDH8 12
CDHR3 2
CDHR5 22
CDIPT 23 19 21 19
CDK14 23 21
CDK17 17
CDK18 1.5
CDK19 21
CDK2 6
CDK20 2
CDK2AP2 3
CDK4 7
CDK5RAP2 0.5
CDK5RAP3 6.167
CDK6 8
CDK7 21 18
CDK8 22
CDK9 2
CDKAL1 22
CDKL1 4.5
CDKL2 23
CDKL5 20.5
CDKN1A 19 22 20 21.5 19
CDKN1C 0
CDKN2AIP 23.5
CDKN2B 21.5 22
CDKN2C 2.167
CDO1 4 3 3
CDON 1
CDR2 23
CDS2 10.5 13.5
CDSN 9.5 9
CDX4 23
CEACAM1 5.5
CEBPA 11 15
CEBPB 5.5
CEBPG 23 22
CECR2 14 15 12
CECR6 0
CELF1 10.5
CELF2 7 4 12.5
CELF4 21 23
CELSR1 9 20.5 19 7 13
CELSR2 23
CEND1 0
CENPA 20 16 20
CENPB 15
CENPC1 19
CENPL 12.5 13
CENPP 22
CENPQ 4
CEP120 17 10
CEP128 23
CEP135 19.5 19
CEP19 7 6 22.5 8
CEP290 20.5 22.5
CEP350 21
CEP41 5 22
CEP44 21.5
CEP57 23.5 22
CEP63 21
CEP68 20
CEP76 5 6.5
CEP78 22 22
CEP85 8
CEP85L 22
CEP89 19 7 16
CEP95 22
CEP97 13 13 11 13
CEPT1 21.5 20.5
CERK 7
CERKL 15 11 18.5
CERS2 21 23
CERS4 19
CERS6 23.5
CES1 1 22
CES1D 11
CES1F 23
CES2G 21
CETN3 7
CETN4 23
CFC1B 9
CFD 21
CFL1 9
CFL2 10 18 12 12 16.5 10 11
CFLAR 9.5
CGN 13.5 6
CGNL1 10.5
CGRRF1 7
CHAC1 8
CHAMP1 11
CHCHD10 10.5
CHCHD3 11
CHCHD5 11
CHCHD7 6 9
CHD2 13
CHD3 1
CHD4 6.5 11
CHD6 7 12
CHD7 7.5
CHD9 10.5
CHEK2 20
CHI3L7 12
CHIC1 7
CHID1 12
CHKA 11.5
CHKB 22
CHMP2A 19 16
CHMP2B 23 11
CHMP5 8
CHN1 4 5 4
CHN2 18 18
CHORDC1 22
CHP 17
CHPF2 20 21 13
CHR4 8
CHR6 10
CHRAC1 14 10 10 11.5
CHRM2 6 3
CHRNB1 21.5 0
CHST1 19
CHST11 6.5
CHST13 5.5
CHST15 5
CHST2 9.5 10
CHST3 2
CHST8 19
CIAPIN1 22 17 21
CIB4 18
CIDEC 19
CIITA 18
CIRBP 0 22
CISD1 0
CIT 7.5
CITED2 10 11.5
CKAP4 0
CKAP5 2
CKB 6
CLASP1 22 22.5
CLASP2 23 23
CLCA4 23
CLCC1 22.5 21
CLCN2 16 18 18 15 14.5 16
CLCN3 22 2
CLCN5 19
CLCN6 7.5 10 1
CLCN7 9 9.5
CLDN1 9 15.5
CLDN10 4 22 23
CLDN11 10
CLDN12 23
CLDN15 5
CLDN2 12
CLDN5 21
CLDN7 14
CLDN8 18 15
CLEC2H 19 17
CLEC3B 8
CLEC4M 20 23
CLEC5A 6
CLIC4 4
CLIC5 4
CLINT1 14
CLIP1 18.5 15 17
CLIP2 16 22
CLK2 23 12
CLK3 8
CLMN 10.5
CLMP 22 23
CLN3 9.5 16
CLN5 13.5 14
CLN6 8
CLNS1A 22.5 11.5
CLOCK 23 7
CLPB 20 20.5 3
CLPP 9
CLPTM1 10 12.5 23.5 3.5 14
CLPX 22 13.5
CLRN1 12 10 11 11
CLSTN1 8 15 10.5 8 12 15.5
CLSTN3 16 6
CLTB 12 6 20
CLTC 6.5 9 13.5
CLYBL 13 14.5
CMA1 10 11 21 12.5 10 10.5
CMAH 18 9
CMBL 12
CMC2 7
CMIP 22
CML1 1
CML2 6 19 12
CML5 13.5
CMPK2 17
CMTM3 11
CMTM4 9 10 10 9 10 12
CMTM6 21.5 21 17
CMTM7 5.5
CMTM8 8 18
CNBD1 10 12
CNBP 10 12.5 11
CNDP1 19
CNDP2 9 11 4.5 9
CNEP1R1 8
CNIH 10
CNIH4 12 21 5
CNKSR2 16 17 18 16 14 16 13 16.5 15.5
CNKSR3 21
CNN1 9
CNN3 6
CNNM3 11.5 8
CNNM4 12
CNOT2 12 10
CNOT6 0
CNOT7 15 15 12 14 15 15 15.5
CNP 5
CNPPD1 7 7 11 6
CNPY2 2 12 4
CNPY4 23
CNR1 7 9 9
CNTFR 4 7
CNTN1 23
CNTN5 23
CNTP5C 1
COASY 22 14
COBL 5.5
COBLL1 17
COBRA1 23
COG5 18 20 20.5 20.5 22.5 17
COL12A1 6
COL13A1 10
COL15A1 9
COL18A1 0
COL1A1 8 7 7 9 9
COL27A1 16 17 10 19.5
COL3A1 4
COL4A1 13 14
COL4A2 21 18
COL4A3 10
COL4A4 15 23
COL5A1 22 10
COL5A2 11.5
COL5A3 3
COL6A2 6
COL6A3 5
COL6A6 5.5
COL8A1 4
COLEC12 10
COLQ 8 9.5
COMMD10 20
COMMD4 18.5
COMMD5 7 7
COMMD6 19 17
COMMD7 14
COMT 20 22
COPE 0.5 22
COPG1 18 19
COPG2 22.5
COPS4 12.5
COPS6 22
COPS7A 0 11
COPS8 23
COPZ1 5 10 9 8
COPZ2 6 11
COQ10A 10.5
COQ10B 10
COQ2 14.5
COQ4 6.5 11
COQ5 7 17
CORIN 22
CORO1A 13.5 14.5 11 19 19
CORO1B 3
CORO2A 12.5 8 21 16.5 21 18
CORO6 1
COX10 10
COX14 7
COX18 8 8.5
COX19 10 11 12
COX20 23
COX4I1 21
COX4I2 23 10
COX6A1 12 8 10
COX6B1 11
COX8A 9 10
CP 3
CPA1 8.5
CPA3 21 7.5
CPE 19
CPEB1 9 12
CPEB2 21.5
CPEB3 21
CPEB4 17 18 19 18
CPLX2 14
CPLX4 22.5 7 21
CPM 0.167 21 18 15 21 20.5
CPN2 0
CPNE1 12 11 12 10.5 12.5 12 13
CPNE2 5.167 12
CPOX 14
CPQ 9.5
CPSF1 20.5
CPSF3 8 4.5
CPSF3L 15
CPSF4 7 10 11 5 8
CPT1A 0
CPT2 15
CPXM1 19
CRADD 11 7.5
CRAT 12
CRCT1 23
CREB1 8.5
CREB3L1 9 10 8
CREB3L2 23
CREBBP 5.5 5.5 4.5 1 5
CREBL2 13 16 15
CREBRF 4
CREG1 10 10 6 11.5
CRELD1 12 7
CRELD2 13
CREM 9
CRIM1 8.5 10 11
CRIP2 11.5 11
CRISPLD1 3.5 3
CRLF3 12
CRLS1 16
CRMP1 12 7.167
CROT 9
CRP 23
CRTAC1 4.5
CRTC2 4 6 6 3.5
CRTC3 22 17
CRY1 11 12 13 13 18.5 11.5 13
CRY2 5 21
CRYAB 10 11 14 0
CRYBG3 12 12.5
CRYL1 3
CRYM 22 23 21
CRYZ 1.5 13.5
CS 0 12
CSAD 21 21 21.5 21.5 20 21.5
CSDA 18.5
CSDC2 20
CSE1L 20.5 9
CSF2RB 6.5 1.5
CSF3R 21
CSGALCT1 20 14 21
CSL 18 0 13.5 12
CSMD2 20.5 19.5 21.5
CSMD3 16.5
CSNK1E 8
CSNK1G1 2.5 9
CSNK1G3 17
CSNK2A2 17
CSPG4 20 12 12 15 14 12
CSPG5 9
CSRNP1 18 23 23 1.5
CSRP1 1 2 5 4 18 23 22 10 21
CSRP3 20
CST3 2 3
CST8 12
CSTAD 17
CSTB 12 16
CSTF2 13 21.5
CSTF3 3.833 3.833
CT025673.2 9
CT573086.1 8 7 10 9.5
CTBP1 13.5 12 11
CTC1 10.5 17 20
CTDP1 7.167 20 20
CTDSPL 10.5
CTF1 15.5 9
CTGF 22 18
CTH 22 13 5.5
CTHRC1 16
CTIF 21
CTLA2A 11 21.5
CTNNB1 19 19
CTNND1 20.5
CTNND2 14
CTNS 10
CTPS2 21
CTSA 21
CTSC 6 7 9 9 8.5
CTSF 12.5
CTSH 22.5 21 2
CTSL2 22
CTSZ 9.5 10
CTTNBP2 22 12 22
CUEDC1 23.5
CUEDC2 10
CUL1 22.5
CUL2 6 4 4 0
CUL7 13 12
CUL9 23 23
CUTA 3.5 22
CUTC 20
CUX1 10
CUX2 11 12 9 14.5 9 16
CWC22 5 21.5
CX3CR1 11.5
CXADR 0 12.5
CXCL12 4.5
CXCL13 12
CXCL14 23
CXCL15 0 21
CXCL16 22.5
CXCL6 21
CXCL9 9
CXCR4 22
CXCR7 7.167
CXORF26 22.5
CXORF38 23.5
CXXC5 8 10
CYB561 9
CYB5A 6.5 8.5 8.5
CYB5B 0 21 8
CYB5D2 23 9
CYB5R2 11
CYB5R4 23 2 1
CYBASC3 0 0 2 0 0
CYBRD1 2 0
CYC1 22.5 14
CYFIP2 13
CYGB 22.5 21
CYLD 5 21 0 3
CYP17A1 22
CYP1A1 23 22
CYP1B1 22
CYP21A2 9 20.5 12
CYP24A1 11 12 12
CYP26B1 8.5
CYP2B6 23
CYP2B9 7 7
CYP2C67 12
CYP2C68 10
CYP2D22 18 14
CYP2D37-PS 8 20.5
CYP2D6 9 9.5 22
CYP2E1 8
CYP2G1 4
CYP2J9 23
CYP2R1 16 17 11
CYP2U1 7 8 11
CYP39A1 22.5
CYP3A13 8
CYP4A28-PS 12 12 16
CYP4B1 23 0
CYP4F12 23.5 15
CYP4F22 20
CYP4F3 19 23.5
CYP4V2 1
CYP8B1 13 2.5
CYR61 8.5 3.5
CYS1 16
CYSLTR2 18
CYSTM1 18 18.5 18
CYTH1 21.5
CYTIP 0 3
CYTL1 7.5 11 7.5
CYYR1 23
D030046N08RIK 11 3.5
D130007C19RIK 12
D2 18 21
D2HGDH 11
D630013G24RIK 8 9.5
D630029K05RIK 23
D730003I15RIK 22 22 20 20
D730039F16RIK 12
D930048N14RIK 22 17
DAAM1 19 20 7
DAB2 11.5
DAB2IP 16
DACT1 20 22 22.5
DAF2 3
DAG1 11
DAK 19
DALRD3 9 9 10 8.5 10 9 10
DAO 22 3 23
DAP 20
DAPK1 10
DAPK2 3 3
DAPK3 8
DARS2 13
DAZAP2 18
DBI 16.5
DBP 20
DBT 17 3
DCAF12 23
DCAF15 17 18 22.5 20 18
DCAF4 1 6 6 4 11
DCAF6 15 16 14.5 18 16
DCAF7 2.5 3
DCAF8 0 3 23
DCBLD1 20
DCDC2 13
DCDC5 23
DCHS1 13
DCLK1 11
DCLK2 23.5
DCLK3 9
DCLRE1A 20 21.5
DCLRE1B 12
DCN 22 2 2.5 1.5 0 23
DCTD 13
DCTN2 4.5 22
DCTN3 21 14 4
DCTN5 7
DCTN6 22
DCTPP1 7.5 8 11
DCUN1D3 5 4 23 1
DCUN1D4 8.5
DCUN1D5 11
DCXR 6
DDAH1 9 7
DDAH2 7.5 9.5
DDB1 5 4
DDC 10 13
DDHD1 13
DDHD2 9
DDIT4 8 23
DDIT4L 23 22 18
DDO 17
DDR1 10.5 20
DDR2 20
DDRGK1 15
DDX1 17 15.5
DDX17 8 17 15
DDX28 16
DDX39B 8.5 9
DDX3Y 7 14.5
DDX46 16
DDX49 15
DDX6 3 19
DDX60 6
DECR2 23
DEDD 19 14
DEDD2 10 22.5 15
DEF8 17 17
DEFB1 16
DEFB13 23
DEGS1 2
DEGS2 6
DENND1A 13
DENND1C 18
DENND2D 14.5
DENND4A 11 16.5
DENND4B 21 21 19 20.5
DENND4C 5
DENND5B 20 21 23
DEPDC1B 14 17 3 23
DERL1 10 0
DES 22
DEXI 7.5
DFNB31 2.5
DGAT1 1
DGAT2 21 22
DGCR14 11
DGCR8 8 0 4
DGKA 11.5
DGKB 21
DGKD 12
DGKG 17 23 14
DGKH 0
DGKI 23 7
DGKQ 7.5
DGKZ 11.5 4
DGUOK 5.5 14.5
DH3 20
DH6 13 13
DH7 0
DH9 5
DHC12 2 7
DHCR7 15.5
DHRS1 22
DHRS11 18
DHRS2 12
DHRS3 8
DHRS7B 4
DHRS9 20 21 21 19 17
DHTKD1 22 0
DHX29 10 11
DHX32 11
DHX33 4 2
DHX35 11 4
DHX36 21
DHX37 6 3
DHX40 9
DHX58 8
DHX9 11
DIABLO 8.5
DIAPH2 23
DIAPH3 17 13
DICER1 4
DIDO1 9 8
DIMT1 13.5
DIO2 23.5 7
DIP2A 0 1 1.5 2 1.5 23
DIP2B 3
DIP2C 17 20.5
DIRC2 5
DIS3L 19
DIS3L2 15
DISP1 0
DISP2 16
DIXDC1 16
DJA1 21
DJA2 22
DJA4 4.5
DJB11 0 21.5 22.5
DJB14 22
DJB2 10 18
DJB4 0
DJB9 1 1 5
DJC1 8.5 21.5 8.5
DJC10 5
DJC12 11
DJC13 3
DJC14 4.5
DJC18 0.5 4.5 4 4 22.5
DJC22 23 2 4 1
DJC24 22
DJC28 22
DJC3 22 19 17
DJC30 0.5 23 1.5
DJC4 8
DJC5 9
DJC5G 10
DJC6 15
DK 0
DKC1 12.5
DKK2 22 23
DLC1 18 11.5
DLEU7 23.5
DLG1 19
DLG2 11 11
DLGAP1 7
DLL1 8.5
DLL4 9
DMC1 19 22
DMD 20.5 0
DMP1 0
DMTF1 19
DNM1 14 14
DNM1L 6
DNM2 6.5
DNM3 5
DNMT1 21
DNMT3A 11
DNMT3B 12.5 18 12 13
DNPEP 8
DNTTIP1 11
DOC2B 5.5
DOCK1 20
DOCK10 21 2
DOCK11 9 11 9.5 7 12
DOCK2 1
DOCK4 21
DOCK5 9 7.5
DOCK6 10 12.5
DOCK7 21
DOCK8 12 16
DOCK9 15
DOK6 8 19
DOK7 4 2
DOLPP1 22.5 3 21 23
DOPEY2 13.5 14.5 15
DOT1L 23 23 23.5
DPCR1 5.5
DPEP1 12
DPM3 11.5
DPP10 12.5
DPP8 12
DPP9 0 1 2
DPT 6 6
DPY19L1 7
DPY19L3 8
DPYD 6
DPYSL2 7
DQX1 10
DRAM1 22
DRAM2 23 22 21 20 16.5
DRD4 9
DRP2 22.5 23
DSC2 22
DSCR3 11.5
DSCR6 21
DSE1 23
DSE1L1 22
DSE2 8
DSE2B 17
DSG2 21
DSN1 11.5
DST 1
DSTN 20
DSYN1 22
DT 22
DTNBP1 22.5 20
DTX1 7
DTX2 12
DTX3L 7
DTX4 6.167
DTYMK 18 19 19 20 20 17 18 17 18
DUS2L 14
DUS4L 0
DUSP1 22
DUSP10 12 22.5
DUSP11 4.833 8 0
DUSP12 0
DUSP14 19 11.5
DUSP15 22 22 21
DUSP16 10.5
DUSP19 18.5 23 21.5 21
DUSP6 20
DUSP7 0.5
DUSP9 5
DVL3 9
DYM 9
DYNC1H1 5 5
DYNC1I2 7.5 16
DYNC1LI1 18
DYNC2H1 22
DYNC2LI1 10
DYNLL1 2
DYNLL2 11
DYNLRB2 23
DYRK1B 8 4 23.5
DYRK2 10
DYSF 7
DZIP3 10
E030019B06RIK 7.5 11 8
E230001N04RIK 0
E2F2 12.5 15
E2F5 11
E2F6 16
E2F8 8 2
EAF1 7 2
EAPP 18 7
EARS2 2.5
EBF1 7
EBF3 15 21 11 11.5 20
ECE1 22
ECHDC1 1 2 23 0 0 22
ECHDC2 23 22.5 1
ECHDC3 20
ECI1 19
ECI2 1 2 22 1 22 23
ECM2 22 22
EDA 7
EDC3 6 9
EDC4 22.5
EDEM1 20
EDEM3 20
EDN1 22.5
EDN3 22
EDNRA 18 23
EDNRB 23
EEF1A2 6
EEF1E1 14
EEF1G 9
EEF2K 8 8.5
EEPD1 20.5
EF2 14 14.5 14 14 14.5
EFCAB1 20.5
EFCAB2 2
EFCAB4A 21
EFCAB4B 23 23
EFEMP1 19.5 16
EFEMP2 18
EFHD1 3.5
EFHD2 0 23
EFNB1 6
EFNB2 23 1 0 20
EFNB3 0 16
EFR3A 0 0 0.5 1 0 23 1
EFR3B 0
EGFL6 4
EGFL7 23
EGFLAM 15.5 18
EGFR 13 15 13 21 14 11.5 11
EGLN1 20
EGLN2 1
EGLN3 18 23
EH 22
EHBP1 9 10.5
EHBP1L1 4
EHD1 12 12.5 14 9
EHD2 15.5
EHD3 14.5 15
EHD4 22
EHHADH 11
EHMT2 1 7
EI24 4 23
EID1 14 9
EID2B 15
EIF1AX 8 0
EIF1AY 10
EIF2A 19
EIF2AK1 11 21 0
EIF2B1 11 13 12
EIF2B2 21
EIF2C2 22.5
EIF2C3 5
EIF2C4 3
EIF2D 19
EIF3B 22 1
EIF3D 4 2
EIF3E 21 22
EIF3F 11.5
EIF4A2 22.5
EIF4B 1 17
EIF4E2 3 2
EIF4E3 6.5 8.5 10 10.5
EIF4EBP1 21.5 16 22.5
EIF4EBP2 13 13 14 15 12 13 13
EIF4EBP3 12.5 6
EIF4ENIF1 2.5
EIF4G1 23.5 17 0
EIF4G2 21
EIF4G3 21 20
EIF5 8 11 9 11
EIF5A2 6 2.5
ELAC1 22
ELAC2 3
ELAVL1 2
ELAVL3 6
ELAVL4 2
ELF1 20.5 22 22
ELF2 6
ELK3 20
ELL 0
ELL2 22 21
ELMO1 22
ELMO2 5 14.5
ELMOD1 23.5 3.5 5.5
ELMOD2 12
ELMOD3 4 5.5 18.5
ELN 20 12
ELOVL1 0
ELOVL2 23 10
ELOVL3 8 11.5
ELOVL5 20 23
ELOVL6 19
ELOVL7 7 9 6 8 8
ELP2 8 10
ELP4 21.5
ELTD1 5.5
EMB 7
EMCN 19 16 19 13
EMG1 21 0 16
EML1 21
EML2 1
EML3 5
EML4 8
EML5 21 11
EMP1 10
EMP2 10 23
EMR4 12
ENDOD1 5
ENDOG 7
ENG 22 19
ENGASE 21 23 22 20
ENO3 5.833
ENOX1 20
ENOX2 0
ENPEP 17 21
ENPP1 6 8 7
ENPP2 20.5 21 22 23 22
ENPP3 19
ENPP5 16
ENPP7 2
ENTPD1 21
ENTPD2 19 19 5
ENTPD3 19 23.5 19
ENTPD5 17
ENTPD6 22 10 9
ENTPD8 12
ENY2 12
EOGT 11 12 21 17
EP300 23.5
EP400 1
EPAS1 0 8
EPB41 10
EPB41L2 16
EPB41L3 10 22
EPB41L4B 22.5 22 21 0 21 0
EPB41L5 18
EPC2 9 9 7.5
EPDR1 3
EPG5 23 23 1 21 2
EPHA1 0
EPHA3 4.5
EPHA4 12 12 11
EPHA5 9
EPHA6 13 13.5 13.5
EPHA7 22 10
EPHA8 22 0
EPHB1 16.5
EPHB4 20 18 19
EPHX1 2
EPHX3 14 20 14 12.5
EPM2A 12.5 11
EPM2AIP1 13 8
EPN2 23.5 1
EPRS 17
EPS8 10 12.5
EPS8L2 10 8
EPT1 0
ERAL1 14.5 5.5
ERBB2 9.5 8
ERBB2IP 8
ERBB3 22 2
ERBB4 9 11 11 15 13 13
ERC1 21.5
ERC2 23 23
ERCC1 20.5 18.5 21.5
ERCC5 22 21 21 0.5
ERF 18 13
ERG 22
ERGIC1 0
ERGIC2 22 22.5
ERI1 5 23
ERI2 7.5
ERLIN1 0
ERLIN2 8
ERMN 5
ERMP1 22
ERO1L 22
ERP29 23
ERP44 21.5 18 19
ESM1 4 6
ESR1 1
ESR2 2
ESRP2 8 8
ESRRA 15
ESRRG 9
ESYT1 22
ESYT2 23
ETFB 19.5 23
ETFDH 23
ETHE1 11.5 19
ETNK1 20 2
ETNK2 17
ETS1 19
ETS2 13.5
ETV1 22
ETV5 21 21.5
ETV6 3.5
EVI5 19
EVI5L 14
EXD1 9 12 11
EXD2 9
EXOC1 10.5 5 14.5
EXOC2 7 9.5
EXOC3 16
EXOC4 6
EXOC5 10
EXOC6 19.5
EXOC6B 9
EXOC8 9 10 9 7 7 9.5 10
EXOG 23 7 10.5
EXOSC1 21.5 0
EXOSC2 2
EXOSC3 21 20.5 22
EXOSC7 22.5
EXOSC8 21 19
EXOSC9 0.5
EXPH5 13
EXT2 4
EXTL1 9
EXTL3 2
EYA1 4 0
EYA2 2
EZH1 5
EZH2 19
F11R 13
F2R 22
F2RL1 7.5
F3 19 20
F730043M19RIK 20.5 4
F830001A07RIK 1
FAAH 10 11 11
FABP1 6
FABP2 21 20
FABP7 0
FADS1 17
FADS2 23
FADS3 11
FADS6 23
FAF2 3 1 1 2 4 0 7
FAH 21 13
FAIM 23
FAM100A 6 7
FAM101B 23.5 4 22
FAM102A 7 9 9 7.5
FAM107A 17
FAM108A1 23
FAM108B1 22 1
FAM108C1 2
FAM110B 16 23
FAM111A 20
FAM114A1 22
FAM115A 19
FAM116B 8
FAM117A 11
FAM117B 7
FAM120A 2 22 0 3 3
FAM120B 22
FAM120C 6
FAM123B 5 8
FAM123C 3 5
FAM124A 16.5 19 19.5 17 6
FAM124B 18
FAM125A 23
FAM125B 2
FAM126B 0 1
FAM129A 11
FAM132A 21 2.5 5 22
FAM134A 12
FAM134B 21
FAM13A 19
FAM13B 16 19 22 20
FAM149B1 22.5
FAM150B 15
FAM155A 22.5
FAM160A1 6.167
FAM160A2 9
FAM161B 20
FAM162B 15
FAM163A 14 5 13
FAM169B 14.5
FAM171A1 12 14 12
FAM171B 3
FAM172A 15 12 13.5
FAM173B 20
FAM174B 21 22 3 0 21
FAM175B 17
FAM178A 20 20 18
FAM184A 13
FAM188A 22
FAM188B 23.5 23
FAM189A2 10
FAM190B 17
FAM195A 2.5 6
FAM195B 4
FAM198A 22.5
FAM198B 17
FAM19A1 7
FAM204A 23.5
FAM206A 22
FAM208B 7 9 7
FAM20A 0.5
FAM20C 21
FAM210A 18
FAM210B 6 7.5
FAM213A 21
FAM214A 22 23 22
FAM216A 6 7
FAM219A 19
FAM219B 22.5 21
FAM21A 10 22
FAM26E 21
FAM3C 8 11.5
FAM40B 9
FAM45A 7
FAM46A 11.5
FAM47E 8.5
FAM48A 23
FAM49A 14
FAM49B 9
FAM50A 7
FAM53B 21
FAM54B 0 4
FAM55B 22
FAM55C 1.833
FAM55D 23
FAM57A 13.5
FAM5C 18
FAM63B 15 21
FAM65A 7 8 7
FAM65B 12
FAM69A 5
FAM73A 9
FAM73B 9
FAM76A 11 9.5
FAM78B 0
FAM82A1 0
FAM82A2 2.833
FAM83A 8
FAM83D 16
FAM83F 7
FAM83H 21
FAM84A 0
FAM84B 23
FAM89A 13
FAM96A 13
FAM96B 17
FANCB 12
FAP 23 23 22 0 0.5 23 0
FAR1 17
FARP1 21
FARP2 21
FARSB 7
FAS 23.5
FASN 10
FASTK 6
FASTKD2 21 0
FAT1 2
FAT3 7
FBLIM1 23
FBLN2 5.5 0
FBLN5 22
FBN1 15 15.5 14.5 16 12 15 17
FBN2 18 21 15 19
FBRSL1 4
FBXL13 17
FBXL18 20.5 17
FBXL2 17
FBXL20 12
FBXL21 16 8 0
FBXL3 1
FBXL4 18
FBXO21 2 11
FBXO22 4 5
FBXO25 23 8
FBXO3 22 7 15.5 11
FBXO30 11
FBXO31 4
FBXO32 0 21
FBXO33 7
FBXO34 10
FBXO36 11 13 13
FBXO40 20.5
FBXO44 22
FBXO45 4 22
FBXO6 15.5 2.5 22
FBXO8 16 6 17
FBXW2 19 20
FBXW8 19 15
FBXW9 2.5 4.5
FCAMR 13
FCER1G 21 12
FCGR2B 22
FCGRT 5 6 6
FCHSD1 10 14 12
FCHSD2 5
FCRL1 6 22.5
FDFT1 10
FDPS 23 9
FDX1 20
FDXACB1 12
FEM1A 14 12 12.5 16
FEM1C 3
FER 16 22
FERMT1 15 22
FERMT2 23
FES 12.5
FFAR2 16 14
FGA 7 10
FGB 20
FGD4 5.5
FGF1 2
FGF10 5.5
FGF11 1
FGF13 20 20 20 22.5
FGF16 1
FGF18 14 21
FGF9 0
FGFBP1 21
FGFR1 21.5
FGFR1OP 11.5
FGFR2 22
FGFR3 22.5
FGFR4 21
FGFRL1 22
FGG 14
FGGY 17 21
FH 22 3.5
FHAD1 6 0 7
FHDC1 23 18
FHIT 21
FHL1 7
FHL3 14
FHOD3 0
FIBIN 0
FIBP 22 2
FIGF 12
FILIP1 5
FILIP1L 23
FIP1L1 22 22 23.5
FIS1 2
FITM1 9 23
FITM2 23 21
FKBP10 20 3.5
FKBP1A 3
FKBP1B 21 19
FKBP3 20 22.5 23 20.5
FKBP4 18 18
FKBP5 14 14
FKBP7 5
FKBP8 0
FKTN 20.5 19
FLCN 8
FLNB 21
FLOT1 10
FLOT2 0.5
FLRT1 6
FLRT3 20
FLT1 21 22.5
FLT4 23
FLVCR1 6 7
FLVCR2 18
FLYWCH1 11
FMN2 22 3
FMNL1 23
FMNL2 6 0
FMNL3 9
FMO1 10 5.5 12 15 12 11
FMO2 13
FMO3 15.5 20
FMO4 23 22.5
FMO5 19 6
FMOD 23
FMR1 6 16
FN1 21
FN3K 6 23 3
FN3KRP 2 23.5 3 4
FNBP1 20
FNDC3A 17
FNDC3B 23.5
FNDC4 10 12.5 12 8.5
FNIP1 6 8
FNIP2 7 8 3.5
FOLH1 16 0
FOLR1 23 22
FOLR2 8 8 16 9 11.5 18 10
FOPNL 10
FOSL2 16 0.5
FOXA2 8 11.5
FOXA3 22 1.5 7 22
FOXC1 21 21 23
FOXJ2 19.5 21.5
FOXK1 9 7
FOXK2 3.5
FOXN2 7
FOXN3 20.5
FOXO1 1 0
FOXO3 11 3.5
FOXP1 11 11 11 13 11 12 12 13 10 11.5
FOXP2 21
FOXRED2 4 20
FOXS1 3
FPGS 22
FPGT 1 17
FRA10AC1 0
FREM1 18 17
FRG2 3 23.5 20
FRMD4A 21
FRMD4B 19
FRMD5 20 1 22 22
FRMPD1 12
FRRS1 20
FRY 20
FRYL 9 11.5 23.5
FRZB 16.5
FSCN1 6 7
FSIP1 12 21
FST 17
FSTL3 12
FTH1 19 19
FTSJ1 8
FTSJD1 0
FUBP1 22
FUBP3 11
FUCA2 22
FUK 0
FUNDC1 10
FURIN 15 18.5 13 16 11
FUS 22 23
FUT2 23 22 1.5 22 23 23
FUT8 23 22 21.5
FV1 8.5 10.5
FXR1 7 17 9 10 9 9.5
FXYD1 22.5 23 18.5
FXYD4 18 21 22
FXYD5 9
FYB 9.5
FYCO1 22 23 14.5
FYN 15
FZD1 22
FZD2 9
FZD3 23 8
FZD4 1 0.5 22.5
FZD7 20 22
FZD9 23 20 22 15 22
G0S2 4 12
G12 7 8 11
G13 23
G3BP2 12 13
G630090E17RIK 21
G6PC 22
G6PD 6 1 4 23
G6PD2 17
GAA 0
GAB1 9
GAB2 11
GABARAPL1 8.5 15 10
GABBR1 2
GABPA 0 9
GABPB1 23 12
GABPB2 23 0
GABRA3 13
GABRB1 16 16
GABRB2 2
GABRB3 23.5
GABRE 19
GABRQ 19.5 10 0
GABRR2 19 17
GADD45G 10 5
GAK 7 7 7 22
GALE 9 8
GALM 9 10 22
GAINS 9 14.5 15 14
GALNT10 18 23.5
GALNT11 14 1
GALNT14 17 0
GALNT3 7
GALNT7 9 12 9
GALNTL1 10
GALNTL4 10
GALT 8.5
GAMT 11.5 10.5
GAP43 8
GARNL3 2 0.5 1 23 0
GARS 12 13
GART 14.5
GAS2 0 7 9
GAS2L3 14 14
GAS6 21 22
GAS7 8
GATA4 8 10
GATA5 6
GATA6 12
GATAD1 22 23.5
GATAD2A 22
GATAD2B 12
GATC 12
GATM 18 18.5 17 18 17 5.5
GATSL2 22
GATSL3 15 0
GBA2 20 16 15 18
GBAS 6 19 15 5
GBE1 11.5 9 13
GBF1 11 3
GBP11 10
GBP4 2
GBP5 1
GBP8 5
GCA 8 4.5
GCDH 6
GCGR 7
GCH1 3
GCK 11
GCKR 5 18 22.5
GCLC 0.5
GCLM 9
GCNT1 15
GCNT2 22.5 6.5
GCSH 14
GDA 23 20.5
GDE1 23
GDF10 7
GDI2 8
GDNF 11
GDPD1 17
GDPD2 0.5
GDPD5 6
GEMIN6 14 11
GEMIN7 21 22
GFM1 11 13.5 16 13 12
GFM2 9 10 8
GFOD1 11
GFOD2 21.5 19
GFPT1 22
GFRA1 10
GFRA2 12
GGA2 13
GGCT 23 3
GGCX 5
GGPS1 21
GGT6 23
GH 9
GHDC 7.5 11
GHR 9 8 8 11 10 8
GI1 6 22.5 21
GI3 22
GIMAP1- 8
GIMAP4 10 19
GIMAP5 10.5
GIN1 17 15 20.5 14 17 19
GIPC1 12 12 11 13
GIPC3 5 3
GIT1 2
GIT2 11 21 3.5
GJA1 7 7 0
GJA5 22 22.5
GJB1 20
GJB2 23
GJB6 22
GJC1 3
GJC2 8 23 23
GJC3 1
GK 0
GK5 19 23 21 22.5
GKAP1 0 0
GKN3 21
GLB1 20
GLB1L2 21 22 6
GLB1L3 7 6.5 8 6 5.5
GLDC 18 19 23
GLI2 4.167
GLIPR2 19.5
GLIS2 19 18.5
GLIS3 8
GLRX 16 12
GLRX2 2 22 23
GLRX5 19.5 20
GLT1D1 2
GLT25D1 21 0
GLT28D2 16
GLT8D2 6
GLTPD2 22
GLTSCR2 21 19
GLUL 10
GLYCTK 19
GM10025 19 11.5 11
GM10032 9.5
GM10038 20 7
GM10167 11.5
GM10250 17 16
GM10287 20
GM10305 11 9
GM10311 2 5.5
GM10319 9 10
GM10357 19 17
GM10565 17 21.5 22
GM10617 22.5 19
GM10629 14
GM10644 2.5 7 7 8
GM10647 16
GM10664 13.5
GM10722 8
GM10737 20
GM10762 7
GM10766 10.5
GM10768 6 0
GM10782 15
GM10787 17 18
GM10800 14
GM10801 7.5
GM10804 18
GM10845 19 14 12.5
GM10863 0 12
GM11428 0
GM11451 18 16
GM11567 19
GM11709 15
GM11942 22
GM11971 23.5 10
GM12026 0
GM12060 23 0.5 2 21 23 23
GM12181 8.5
GM12201 17
GM12202 22.5
GM12222 8 8 7.5 10 11 11.5 10 4.5 8.5
GM12247 10 21.5
GM12258 9 18 10
GM12642 10
GM12689 8 9
GM12696 22
GM12699 6.5 7 21
GM12794 6 7 6
GM12902 8.5 11.5
GM13152 8.5 8
GM13359 6
GM13375 9
GM13397 14
GM13436 21.5 23 19.5 20
GM13440 23.5 21
GM13487 8 8
GM14006 11 12 13 12 13 12 12 11 12 11 10.5 12
GM14150 14 14 13 13 15 13 12.5 14 15 13 11 14
GM14296 10 11 11 11 12 10 12 11 11 11 10
GM14403 21.5 21 22 19
GM14639 7
GM14830 19 20
GM14964 0
GM15024 11
GM15401 4 23 4 21 6
GM15440 21 23 22 22.5
GM15441 1 21 1 2 5 23
GM15470 10
GM15514 23 23
GM15542 22
GM15770 11 2.5
GM15998 16
GM16042 1 23 16
GM16223 19 20
GM16314 12.5 17
GM16373 15 16 16 13 16 14 13
GM16425 23 22
GM16432 21 1.5
GM16493 7
GM16516 10.5
GM17252 9 9.5 8.5
GM17383 23 9.5 17 10
GM17484 22
GM17535 21 11
GM19840 21
GM20396 5 4 4 5 22.5 6
GM20695 9 12
GM266 23 22 23 21 20.5 21
GM2A 18.5
GM3571 21 1 21 20 23
GM4759 21 1 21 22
GM4788 11
GM4875 0
GM4876 4
GM4952 0.5 21
GM4956 23 22 18
GM498 5.5 21 23
GM4989 4.5
GM5393 23
GM5405 22 22
GM5406 21.5
GM5535 10
GM5546 22 11.5 4
GM5548 18.5 16.5
GM609 14
GM6116 16.5
GM6180 21.5
GM6181 22.5
GM6245 22
GM6471 3 5.5 9 3.5
GM6640 9
GM6728 6 3 2
GM6762 21 2 2
GM6829 8
GM7091 13 3 14 12.5
GM7108 23
GM7278 23
GM7293 23 23 2 19 23 22
GM7820 23
GM7887 5 12 8.5 7 1 8 10
GM8098 10 9.5
GM826 22
GM839 16
GM8682 22
GM884 16 18 16
GM9434 9.5
GM9750 14 15.5 7.5
GM9930 9
GM9945 18
GM9947 5.5
GM9949 13.5 10 13
GM9951 4 7
GM9956 20
GM9958 6 15
GM9968 8 9 9
GM9974 9 13
GM9982 8
GM9996 4
GMCL1 12
GMEB1 10.5
GMEB2 6.5
GMFB 22
GMIP 12 14
GMNC 22.5 23.5 0 22
GMPR 23 2 23
GMPR2 17
GNB1 2.5
GNB2 7
GNB2L1 22 21.5
GNE 6.5
GNG12 8 10 9 11
GNG2 10.5
GNGT2 7 23
GNL1 15.5
GNL2 20 21.5
GNPAT 0 4.5
GNPDA2 7 7.5
GNPTAB 13
GNRH1 17
GNS 8 11
GO1 2 22 3.5
GOLGA4 22 1.5
GOLIM4 22.5 0
GOLPH3 5.5 1
GORASP1 17 20 19.5
GOT1 6.5 4.5
GP49A 23
GPAA1 8.5
GPAM 16 23
GPATCH1 10
GPBP1L1 23 4 22
GPC4 8.5
GPCPD1 3.5
GPD1 23 19
GPD1L 21 19 18 17
GPD2 18 16.5 13.5
GPHN 14 13 13
GPI 19 15
GPIHBP1 8 21 20
GPM6B 16 5.5 15
GPN2 20
GPR110 17 12.5
GPR116 20 18 19.5 22
GPR123 13
GPR124 1
GPR125 20
GPR133 12 12
GPR137 19 10 18.5
GPR137C 21.5 8
GPR146 0 7
GPR155 22
GPR157 16
GPR158 1
GPR160 19.5
GPR17 17
GPR182 23.5
GPR19 12
GPR22 20
GPR37 22
GPR4 11
GPR55 8 10
GPR56 3 14
GPR63 19.5
GPR64 6 6.5 7
GPR75 20
GPR75-ASB3 7 7
GPR88 21
GPR97 4
GPRC5B 17 14.5
GPRC5C 18.5 18 5.5
GPRC6A 12
GPRIN3 23
GPSM1 10 9 9
GPSM2 13
GPT 15.5 5.5 14 14
GPT2 6
GPX1 21
GPX3 11 9
GPX4 19
GPX8 1
GRAMD1A 20.5
GRAMD1B 21.5
GRAMD2 0 20
GRAMD3 8
GRAMD4 14.5
GRASP 5
GRB10 11
GRB14 20 20.5 23
GRB7 9
GREM2 15 2
GRHPR 8 11
GRI 18.5 4
GRIA1 22
GRIA3 21 22.5 17 2
GRID1 17 19 14 1 14 20
GRIK5 0 1
GRIP2 13
GRK5 22
GRK6 0.5 7
GRN 19 7.5 11
GRP 12 14 11
GRPEL1 1 22.5 7 6
GRPEL2 12.5
GRPR 8
GRTP1 9 18 21
GS 22
GS 11 8 9.5
GSK3A 23 13
GSK3B 10 9 20
GSPT1 22
GSR 22
GSS 6.5 8
GSTA3 19
GSTA4 23
GSTCD 9 2
GSTK1 3.167
GSTM1 4.5
GSTM2 5.833
GSTM3 11
GSTM4 19
GSTM5 16.5
GSTO2 5.167
GSTT1 3.5
GSTT2 4.5
GTF2A1 2.5
GTF2B 4.833
GTF2F2 6.167
GTF2H2 4.5
GTF2H3 0
GTF2H4 4.833
GTF2H5 4.5
GTF2I 1.167
GTF2IRD1 7.167
GTF3A 1.833
GTF3C1 5.167
GTF3C5 7.167
GTPBP2 1.833
GTPBP8 10.5
GUCY1A2 23
GUCY1A3 11 14 13
GUSB 3 4.5 1 2
GXYLT2 2
GYG1 5 6 6 12
GYLTL1B 19 20.5 19 18
GYPC 22 23
GYS1 9.5
GYS2 6.167
H1F0 11
H2AFV 4.167
H2AFY 9
H2-M9 3.167
H2-Q10 5.167
H2-Q4 5.167
H2-Q5 4.833
H6PD 9
HACE1 15
HACL1 3.5
HADH 3.833
HADHA 0.833
HAGH 11
HAGHL 5.5
HAL 6.167
HAMP 7.833
HAO2 1.833
HAPLN1 11
HAT1 4.833
HAUS4 4.5
HBA-PS4 4.833
HBEGF 7
HBP1 6.5
HBS1L 1
HCAR2 22
HCFC2 4.833
HCN1 2.833
HDAC10 10
HDAC11 1
HDAC3 7.833
HDAC4 1.833
HDAC5 5.833
HDAC6 7.833
HDAC7 4.167
HDAC8 4.833
HDAC9 9
HDC 0
HDGF 23
HDHD3 21
HEATR1 19 23.5 20
HEATR5A 10 20
HEATR5B 7 7
HEBP1 22 13.5
HEBP2 23 7.5
HECA 6.5
HECTD1 20
HECTD2 0.5 7
HECTD3 11
HECW1 18.5
HECW2 4 2
HEG1 23
HELZ 10
HEPH 11.5 23
HERC3 22.5
HERC4 19 22
HERPUD1 21.5
HES6 6 5 9
HEXDC 9 9
HEY1 3 17
HEY2 23
HEYL 18
HFE 22
HFE2 18
HGF 14
HGS 22
HGST 22.5
HHAT 10
HHATL 1
HHEX 20 0.5
HHIP 23.5
HHIPL1 19 21.5 20 1
HIAT1 5
HIBADH 1
HIF1A 17
HIF3A 6.5 7
HIGD2A 17 22
HILPDA 11
HINT3 1 2
HIPK3 22.5
HIST1H1C 10
HIST1H1D 22.5
HIST1H2BD 5 23 20 0
HIST1H2BG 12
HIST1H2BG 22 13.5
HIST1H2BJ 16
HIST1H4D 12
HIST1H4F 7.167
HIST2H2BF 7
HIST2H3A 1 22.5
HIST2H4 17
HIST3H2BB 0.5
HIVEP1 0 16.5 23
HIVEP2 19
HJURP 22
HK2 3 4
HLA-B 21.5
HLA-C 7
HLA-C 19
HLA-DMA 3.5
HLA-DMB 21
HLA-DOA 18 16.5 22
HLA-DOB 22
HLA-DQB1 1 21.5 23.5 11.5
HLA-DRB1 12 21
HLA-E 13.5 13
HLCS 21 23
HLF 1
HLTF 14 11
HLX 15.5 4.5
HM13 7 0
HMCN1 4
HMCN2 10 6.5 0
HMGCS1 3.5
HMGCS2 0.5
HMGN5 22
HMGXB4 22
HMHA1 20
HMOX1 1
HMOX2 5 22 0
HN1 8.5 19 21 13
HN1L 11 11 11.5 12 11 13.5
HNF1A 23
HNF1B 21.5 14
HNRNPA0 7
HNRNPC 4
HNRNPD 11 12
HNRNPH3 10
HNRNPL 12
HNRNPM 23 22 22 1 20.5 20 22 22
HNRNPR 12
HNRNPU 10.5
HNRNPUL1 10
HNRNPUL2 9
HNRPDL 10.5
HOGA1 10
HOMER1 12
HOMER2 10
HOMEZ 7.5
HOOK1 23.5
HOOK3 12
HOPX 17 11
HOXA10 20.5
HOXA5 8 6 11
HOXC8 9 10 10 12 13 11 12 9.5 9 10 9.5 10
HOXD8 7 8 7 8 9.5 7 8 7 8 8 5 8
HP 22.5 4
HPD 23 0 22.5
HPGD 10
HPN 15 20 22 23.5 12.5
HPRT1 13
HPS1 13.5
HPS3 16.5 13 12.5
HPS4 0
HPS5 8
HPSE2 22
HRAS 9
HS1BP3 23
HS3ST1 22 23
HS3ST3A1 23
HS3ST5 2.5
HS6ST3 6
HSBP1 19 22 20
HSD11B1 10 9 10 9 22 7
HSD17B10 4 5
HSD17B11 23 0 0 23 23.5 0 23 0 23 2 0
HSD17B2 21
HSD17B4 16 9 13
HSD17B7 11
HSD3B2 21 0 23.5
HSD3B5 7
HSD3B7 1
HSDL2 11
HSF1 9 11
HSF4 16 19.5
HSP90AB1 16
HSP90B1 15
HSPA12A 22
HSPA13 0
HSPA14 7.5
HSPA1L 23
HSPA4 9
HSPA4L 0.5
HSPA5 17
HSPA8 22.5
HSPA9 20.5
HSPB2 22 21 18
HSPB7 5.5
HSPB8 3
HSPBAP1 12 15
HSPBP1 10 0
HSPD1 6 4
HSPE1 19
HSPG2 21
HSPH1 19
HTATIP2 9
HTR1B 20
HTR2A 8 6
HTR2C 1
HTRA1 6.5
HTRA3 20 17 2
HTRA4 7 10 23
HUNK 0 5.5
HUS1 13
HUWE1 17 18 15.5 13 18
HYDIN 3
HYI 6 23
HYLS1 0.5
HYOU1 21
I 6 7
I830012O16RIK 6 6 23 22
IAPP 19
IARS 0 22 16
IBTK 23 18
ICA1 22
ICAM2 9
ICK 13 11
ICMT 22
ICOSLG 22.5 19
ID1 21.5
ID2 13 10
IDE 22 19
IDH1 19
IDH2 6.5
IDH3A 9
IDNK 1.167
IDO2 23.5
IDUA 8 11
IER3 22.5
IER5 10.5
IFI204 23.5 21 21 1 21 21 21 22 20 21
IFI205 15 15 12 13 18 17
IFI27L2 12
IFI30 10 12
IFI44 4 23
IF147 15 15 16 19 16 11
IFIT1B 12
IFIT3 9
IFITM1 1
IFITM6 2
IFLTD1 6 0 4.5
IFNGR2 21
IFR2 2 3.5
IFRD1 4.5
IFRD2 16
IFT122 21.5
IFT140 14 19 14
IFT172 9 7 15
IFT20 15
IFT27 8 12 12 20 22
IFT80 20 4.5 23.5
IFT81 7.5 8
IGF1 1
IGF1R 23
IGF2BP2 14
IGF2R 8
IGFALS 22.5 23.5
IGFBP1 12 7
IGFBP2 1 22
IGFBP3 18 0
IGFBP4 2.5
IGFBP5 22
IGFBP6 19.5
IGKV2-112 0
IGKV8-21 0
IGSF10 21
IGSF11 5.5
IGSF21 7
IGSF3 16.5
IGSF6 6 1
IGSF8 17 17
IGSF9B 4
IIGP1 4
IKBIP 21.5
IKBKG 21 20
IKZF2 22.5
IKZF3 6
IKZF4 21.5
IL13RA1 22
IL15RA 23
IL17D 17 14.5 18
IL17RB 23
IL18R1 11.5
IL1A 18
IL1R1 7
IL1R2 8 9.5 1 6
IL1RL2 15
IL20RB 15 4
IL23R 23 2 9
IL2RA 9
IL33 11
IL34 2 10 11.5
IL4R 17 13
IL6R 11
IL6ST 16.5
ILDR1 23 23 2 23 0
ILF2 0.5
ILK 20 21
IMP4 15 17 19 15
IMPDH1 4
INCA1 13
INF2 7 22
ING1 0
ING4 1.5 23
INHA 20
INHBA 8.5
INHBC 10.5
INMT 18.5
INO80 21 19
INPP4B 23.5
INPP5A 7
INPP5B 6
INPP5J 2 1
INPP5K 5
INSC 12
INSIG1 12 19
INSIG2 21 21
INSL5 21
INTS10 7
INTS12 23.5
INTS2 21.5 10
INTS3 6
INTS7 18
INTS8 13
INTS9 12 22
INTU 18
INVS 10.5
IP6K3 20
IPCEF1 3 23
IPMK 23.5
IPO11 14
IPO13 10.5
IPO4 9
IPO5 5
IPO9 2 0 0 4
IQCJ-SCHIP1 21.5 3.5 15
IQCK 11 11.5
IQGAP2 23 13
IQGAP3 0
IQSEC1 10 12
IRAK1BP1 7.5 0.5
IRAK2 22.5 16 3.5 2 22
IRAK3 12 13
IRAK4 23.5
IRF2 11 14 13 14
IRF2BP2 11 23
IRF6 20 10.5
IRF7 6 10
IRF9 21
IRGM 0.5
IRGM2 9 12.5
IRS1 12
IRS2 23 22
IRS3 18
IRX1 12
IRX2 0
IRX3 1
ISLR 20
ISM1 7
ISOC1 16
ISY1-RAB43 8
ITCH 11
ITFG3 22
ITGA1 9.5 9
ITGA11 16 9
ITGA3 12
ITGA4 13.5
ITGA5 6.5 7
ITGA6 6 2.5
ITGA7 5 22
ITGA8 11.83
ITGA9 23 0
ITGAL 17
ITGB1 13 1 7
ITGB3 20
ITGB4 2 2.5
ITGB5 21 1
ITGB6 8
ITGB8 6.5
ITIH1 4
ITIH2 9
ITK 0.167
ITM2A 1 2
ITM2B 23.5 8
ITPK1 19
ITPKB 1
ITPR1 15 18
ITPR2 9 8
ITPR3 12.5 13 2.5 11 13
ITPRIP 17
ITPRIPL1 22
ITPRIPL2 10 7
ITSN1 0 4
ITSN2 5 23
IVD 3 0.5
IVNS1ABP 17
IWS1 3.833
IYD 6.5 13
JAG2 12
JAM2 11.5
JAMS 22 22 22 22
JARID2 11 13 12 11 11 11.5 13 11 13
JDP2 5.5 1 21.5
JMJD1C 23
JMJD8 19
JOSD2 2
JPH1 23 19.5
JTB 6.5 23 14
JUN 0.5
JUND 20.5 2 22
KALRN 7 3 2 2
KANK1 6
KANK2 4.5 5.5
KANK3 5.5 10.5 12.5 14 11 8.5 6
KANK4 12 11 14 14 10 6
KANSL1L 8
KANSL3 21
KAT6A 1.5
KAT7 23 5.5
KAT8 20 20 0 21.5
KATL1 22
KAZN 3
KBTBD12 23
KBTBD2 18
KBTBD7 17 2
KC1 11.5 13.5
KC2 6 4
KCMF1 21.5
KCNB1 17
KCNC1 0 22
KCNC3 21
KCND2 21
KCNE2 3
KCNF1 22
KCNG1 14
KCNG4 11
KCNH2 19 21 20 22
KCNIP3 21
KCNIP4 21
KCNJ10 22
KCNJ11 23
KCNJ12 23
KCNJ13 19
KCNJ15 0
KCNJ3 22
KCNJ8 21
KCNK1 21.5
KCNK10 23
KCNK2 20
KCNK3 8
KCNQ2 8
KCNQ4 22
KCNT1 19
KCTD10 13
KCTD13 6.5 11 23
KCTD15 0
KCTD21 21
KCTD5 8.5
KCTD7 22
KCTD9 4.5
KDELC1 18 0 0.5
KDELR1 5
KDELR2 12.5 19 2
KDELR3 2.5 23
KDM1B 23
KDM3A 21 21
KDM3B 14
KDM4A 16
KDM4B 13 13
KDM5A 0 2 0 1 23 1
KDM5B 15 17 16 15 14 13 17
KDM5C 21.5
KDM6B 3.5 23.5
KDR 9
KDSR 5.167
KHDRBS1 21 20 1 5.5 17
KHDRBS3 22
KHNYN 15
KIAA0040 16 18
KIAA0146 13 15
KIAA0182 19 17
KIAA0195 0
KIAA0196 23 19.5 12.5
KIAA0226 23
KIAA0226L 19.5 21 21 22
KIAA0232 12 11
KIAA0247 10 6 5.5
KIAA0284 22 2
KIAA0317 6
KIAA0408 22
KIAA0415 19 21
KIAA0430 23 20.5 23
KIAA0513 14
KIAA0528 20.5
KIAA0556 16
KIAA0564 4.833
KIAA0664 12
KIAA0895 21
KIAA0907 7 11
KIAA0922 0
KIAA0930 5
KIAA0947 0 22 23.5
KIAA1033 21.5
KIAA1109 18
KIAA1161 22 8
KIAA1191 4 1 2.5 3
KIAA1217 6
KIAA1244 6.5 5.5
KIAA1274 19.5
KIAA1279 2.5 23 23 0 12.5 3 0.5
KIAA1324 2.5 23 1 2 1 1.5 4 2 4
KIAA1324L 3
KIAA1328 4.5 3.5
KIAA1377 22
KIAA1383 20.5 23
KIAA1429 18 20 21
KIAA1432 0.5 10
KIAA1456 21
KIAA1462 17 20
KIAA1467 23
KIAA1468 17 21 21 19 20.5 15
KIAA1522 22.5
KIAA1598 11 23.5
KIAA1644 22
KIAA1715 23.5 19.5 23
KIAA1737 18 14
KIAA1797 11
KIAA1841 8
KIAA1967 6.5
KIAA2018 10 6
KIDINS220 19 21 21 21
KIF12 21
KIF13A 11.5
KIF13B 20.5
KIF16B 13
KIF1B 23 10
KIF21A 15.5
KIF2A 2
KIF3A 15 16 17 13.5 12.5 12
KIF5B 15 10.5
KIFAP3 23
KIFC2 15 16 23.5 21
KIFC3 20 18.5 20 18
KIRREL 19.5
KIRREL3 14
KIT 2
KITLG 23
KLB 23
KLC1 13 10
KLC4 23
KLF10 4.5
KLF11 6
KLF12 0
KLF13 21 5.5
KLF15 19 7.5
KLF16 2.5
KLF3 8
KLF5 4 5.5 0.5
KLF6 15 17 13 11 14
KLF9 2.5
KLHDC2 8
KLHDC3 21 23 22 0
KLHDC8A 23
KLHL11 20
KLHL13 1 23 21 22 0.5 20.5
KLHL21 5
KLHL22 19 15 14
KLHL24 2
KLHL29 22 22
KLHL30 22
KLHL32 23.5 23 21
KLHL38 4 22.5
KLHL4 12
KLHL5 10
KLHL7 5 23 21.5
KLHL8 18
KLK3 7
KLK3 6.5 6 22 9
KLK5 13 16
KLRC4-KLRK1 8
KLRD1 16
KMO 21 21.5 20 5
KP1 22 22
KP3 10 10 8
KP4 6 10
KPNB1 22
KPTN 1
KRAS 22.5 19.5 22
KRBA1 9
KREMEN1 1
KRT18 12.5
KRT23 8
KRT7 18 15 17 12 5.5
KRT8 21
KRT80 4 6
KRTAP12-2 10 11
KSR1 9.5
KTI12 18 17 13
KY 19
KYNU 0 22
L3MBTL3 18 17
LACC1 17 15 15
LACE1 5.5
LAD1 23 0 20
LAMA2 18 20 21.5
LAMA3 16
LAMA4 6 9.5 11 8
LAMA5 13 20 15
LAMB1 22
LAMB2 1 21 21 23 21
LAMB3 9
LAMC1 0 0
LAMTOR1 12
LANCL2 23.5
LAP3 21
LAPTM4B 12.5 13 13 13.5
LARGE 10 8
LARP1 21
LARP1B 17 22
LARP4B 0.5 21
LARP7 22
LAS1L 16 0 21 21
LASP1 8.5
LATS2 22
LAYN 23 8.5
LBH 23
LBP 21
LCA5L 22 23
LCK 23
LCLAT1 4.5
LCMT1 0 23.5
LCMT2 1 22
LCN12 22 23.5
LCP1 10.5 17
LCP2 5 7
LDB1 9.5 1
LDB2 10 14 13.5
LDHB 0
LDLR 23 0 21
LDLRAD3 6 8 9 10
LDLRAP1 22
LDOC1L 11
LEAP2 17
LECT2 7
LEFTY1 21 22.5
LEKR1 20.5
LEMD2 7
LENG9 19
LEO1 20.5
LEP 21.5 23 2 0
LEPR 2
LEPREL1 17
LEPROT 21.5
LEPROTL1 2
LETM1 20 20
LETM2 9 13 13
LETMD1 21
LFNG 3 15.5
LGALS1 2.5 23 4
LGALS12 12
LGALS3 22
LGALS3BP 10
LGALS4 13
LGALS8 17 21 5.5
LGALS9 13 10.5
LGALSL 21
LGI2 20 23 22 23.5
LGI4 12 3 22
LGMN 6 1 3 6 2 4 7.5 0
LGR4 11
LGR6 21.5
LHFPL2 5 6
LHPP 3
LHX5 20 16 13 14
LHX6 23 23
LIFR 16.5 19.5
LILRB3 22
LILRB3 21 23
LILRB4 3
LIMA1 23.5
LIMCH1 12 13 13 12
LIMD1 22
LIMD2 13 10
LIMK1 19 17
LIMK2 5.5
LIMS1 20
LIMS2 12 9
LIN37 22 2
LIN52 12
LIN54 21 19
LIN7A 9
LIN7C 18 20.5
LIN9 15 15.5 17 16 15.5 15 13.5 15.5
LINGO2 19
LINGO3 11
LINGO4 12
LIPA 0 0 2 1 1 1
LIPC 20 22
LIPE 7 22
LIPG 15 18 22 18 16 16 14 17
LIPH 21
LITAF 8
LIX1L 6.5 7 0 2
LLGL2 20
LMAN1 23.5
LMAN2 6 7
LMAN2L 7.5
LMBR1L 12 21
LMBRD2 23
LMCD1 2
LMLN 23 8
LMO4 18.5 15 17 18
LMO7 11 9 10.5 10 9
LMOD1 18 8.5
LMOD2 6
LMTK2 16 22 0
LMTK3 23 2.5
LNX1 22 3 0 4 1
LNX2 9
LOC100129480 16
LOC100129924 13
LOC100505478 12.5 13 12.5 13 15
LOC100652815 22 11
LOC375190 23 22.5 23
LOC388630 7 9 7 9 6 4.5 6.5 8.5
LOC441617 19 10 12
LOC646851 11 12.5 14 12 14.5
LONP1 22
LONP2 9.5
LONRF1 11
LONRF2 21
LONRF3 0
LOX 18.5 0 18 17
LOXL1 9.5
LOXL4 1
LPAR2 0 21
LPAR3 8.5
LPAR4 9
LPAR6 13 17 15 16
LPCAT1 17 20
LPCAT2 5 0
LPCAT2B 20 19.5
LPCAT3 3 21 18 19
LPCAT4 20
LPGAT1 5 15
LPHN1 6.5
LPHN2 2 23 2 1.5
LPHN3 3
LPIN1 8 21.5
LPIN2 6
LPIN3 6.5
LPL 9 11
LPP 10.5
LPPR1 6 7 7 5
LRAT 3 0
LRFN3 7 12 0 14
LRFN5 16
LRG1 20 23.5 1 23.5 2 23
LRIF1 18.5
LRIG1 16
LRIG2 22.5
LRIT1 16 19 16 15
LRP1 18 15.5
LRP10 19
LRP11 20
LRP12 23 11 0
LRP2 6
LRP3 23
LRP4 23
LRP5 21
LRP6 23
LRPPRC 3
LRRC1 3.833
LRRC10 23
LRRC14B 21.5
LRRC16A 23
LRRC17 21 21.5 18 23.5
LRRC27 16
LRRC28 23
LRRC3 8
LRRC30 20
LRRC31 2
LRRC32 12 5.5
LRRC36 2
LRRC4 4.5
LRRC41 22
LRRC49 17 20 21 12
LRRC52 21
LRRC55 23 3
LRRC57 17
LRRC58 22
LRRC61 22 23
LRRC8A 4.5 22 11.5
LRRC8B 21 10
LRRC8D 18
LRRC8E 17
LRRFIP1 8 11 9
LRRIQ1 21 5
LRRK1 10.5
LRRK2 21
LRRN1 0 23
LRRN3 14.5 14
LRRN4 7
LRRN4CL 1 22.5
LRRTM2 11
LRRTM3 6 4.5 3 0 1 1
LRTM1 6 8 8
LSM10 17
LSM11 2 23
LSM14A 20 19.5 20.5 18 13.5 18.5
LSMD1 23 14
LSP1 18.5
LSR 16
LSS 22.5 3.5 22
LTA4H 22
LTB 9
LTBP1 18 20
LTBP2 15.5
LTN1 10
LUC7L 21.5 20
LUC7L2 18.5
LUC7L3 14.5
LUM 2.5
LURAP1L 21 11
LUZP1 14
LY6A 20
LY6E 13
LY6G6E 4 23
LY86 14
LY96 10
LYPD6 21 21.5 0
LYPLA2 13.5 14
LYRM1 11.5 10
LYRM4 22.5
LYRM5 16 12
LYSMD2 22
LYSMD3 10
LYST 12 6
LYVE1 3
LZIC 0 22 23
LZTS2 7
MAB21L2 1
MACF1 5
MAD1L1 20.5
MAD2L2 20.5
MAF 11 2 18 18
MAF1 3
MAFB 5 6
MAFF 3
MAFK 7
MAG 11.5 12
MAGED1 17 22 12 12 11 0
MAGEE2 16
MAGI1 22.5 7 5 4 4
MAGI2 13
MAGI3 18
MAGOH 8
MAGT1 0.5 4 22.5
MAL2 2.5
MALT1 0
MAN1A2 3 17
MAN2A1 20
MAN2B2 22.5 23
MAN2C1 9
MANBA 8 10
MANBAL 0 23
MANEA 3 0 3
MANF 23 22 19 0
MANSC4 18.5 18 19.5 19 19 19 19.5 18 18 20
MAOA 21
MAP1A 14 13 15 15.5 13 16 14 14
MAP1LC3A 8 4
MAP2K1 6
MAP2K3 19
MAP2K6 19.5
MAP2K7 16 20 19.5
MAP3K1 22
MAP3K5 23.5
MAP3K6 7.167
MAP3K9 9
MAP4 5
MAP4K2 21
MAP4K4 8.5 8 10.5 12
MAP4K5 7
MAP7 23 22.5 23
MAP7D3 10
MAPK10 15
MAPK12 10 14
MAPK14 9.5 20
MAPK15 5.5
MAPK1IP1 0
MAPK1IP1L 22
MAPK4 9.5
MAPK6 21 23 20
MAPK8IP1 23.5 19
MAPK8IP3 20 15
MAPKAP1 21.5 23
MAPKAPK2 9
MAPKBP1 1 0 2 2.5 1 0 22.5 0 3
MAPRE1 23
MAPRE2 11 20
MAPRE3 8 7 3
MAPT 3
MARCKS 11 11.5 21
MARK2 16
MARK4 3
MARS2 23 2
MARVELD1 14
MASP2 14
MAST1 15.5
MAST2 14
MAST3 20 15 7
MAST4 21.5
MAT2A 14
MATN2 9 8
MATR3 11.83
MAVS 13.5
MAX 9
MAZ 18
MBD1 23
MBD4 11
MBD5 6 3
MBL1 10
MBLAC1 3
MBLAC2 13
MBNL1 16
MBNL2 19
MBOAT1 5 7
MBTD1 21
MC2R 6 4 8 6
MC5R 4
MCAM 11
MCART1 7 7
MCC 9
MCEE 12.5 22 22
MCF2L 2
MCFD2 19
MCHR1 10
MCM10 0
MCM4 6
MCM5 17
MCM7 23 9
MCM8 12 12 10 13.5
MCM9 9
MCOLN1 20 21
MCOLN3 22
MCPH1 0
MCPT4 5
MCTP1 22
MCU 13
MDFIC 16 18 16
MDGA2 19.5 23 23 23.5 0 22 22 22 2 23
MDH2 15
MDM1 5.5
MDN1 22
ME1 10
ME3 22.5
MECOM 21.5
MECP2 23.5
MED11 7.5
MED12 12
MED12L 18 0 20 16 1
MED13 4
MED14 3 6.5
MED15 8 9 9.5 9 10
MED16 4 1
MED20 23
MED23 22
MED24 22.5
MED28 3.5
MED30 21
MED31 19.5
MED6 4.833
MED7 0 8
MED8 5.5 7.5
MEF2D 14
MEGF10 18
MEGF6 23.5 0 22 23
MEGF9 7
MEIS1 22
MEIS2 19
MEMO1 16
MEN1 22.5 23 0
MEPCE 1 0
MERTK 0 19
MESDC2 3 2 3
MEST 0.5
MET 23
METTL10 21.5
METTL13 10 11
METTL16 8
METTL17 6 0
METTL20 22 9 7.5
METTL22 22
METTL24 21
METTL3 19 7
METTL4 20
METTL6 22 21
METTL7A 20
METTL7B 17 19 23 17
METTL8 5.5 1
METTL9 8
MFHAS1 20
MFN1 1.5
MFNG 3.833
MFSD1 15
MFSD12 8
MFSD2A 16 13
MFSD4 3
MFSD5 7
MFSD6 5
MFSD7 9.5
MFSD8 19 21.5
MFSD9 3
MGA 21 0
MGAT1 20 20.5
MGAT4B 5.5 22
MGAT5 20
MGEA5 1.5
MGLL 7.167
MGMT 5.5
MGP 1.833
MGRN1 11
MGST1 22
MGST2 20 22 3.5
MI 18.5 20 22 5.5
MIA2 22.5
MIB1 23
MICAL1 10
MICAL2 10
MICAL3 22 23 0
MICALCL 13 12.5
MICU1 4.5 3 5
MID1IP1 8
MID2 8 17 7.5 12 9.5
MIF4GD 0 23.5 0 3 2
MIR107 23
MIR122A 6 1 23 22
MIR125B-1 8.5 11
MIR128-1 23.5
MIR146 8 9 9 11 10 5 12 9
MIR181B-2 10
MIR218-1 13
MIR218-2 16.5
MIR219-2 8
MIR29B-2 8 11 12 12 11 11.5 12
MIR365-1 14 14 12 12 12 11.5 12
MIR365-2 0
MIR499 6 7.5 6
MIR505 7 9
MIR687 2
MIR694 23.5
MIR701 2 2 2 0 23.5
MIR708 12 16
MIRLET7A-2 4
MIS12 7.5 6 10
MITF 5
MKKS 19
MKL2 18
MKLN1 19 22.5 23.5
MKNK1 22 22
MKNK2 22.5 22
MKRN1 0
MKRN2 19 21
MKS1 11 6
MLC1 0.5
MLEC 20
MLF1 11
MLH1 18.5
MLH3 21 22 23.5 2
MLIP 23
MLL2 6 6.5 23
MLL4 12
MLL5 22
MLLT3 11 11.5 14 17 12
MLLT4 23 22 10
MLST8 22.5
MLXIP 0.5 1 1 23.5 0
MLXIPL 8
MMAA 1
MMAB 19
MMACHC 21
MMD 2 1 3 1.5
MMD2 2
MME 22
MMGT1 21
MMGT2 20 3.5 1
MMP11 7 1
MMP12 13
MMP14 3
MMP15 23
MMP19 10
MMP2 15
MMP23B 2 0.5 0 4.5 4
MMP9 17 16
MMRN2 18
MN1 21.5 0 1 0 23 23.5
MNF1 19
MOB1A 21.5 23 23
MOB3B 9 10 11 6.5 5 7.5
MOCOS 7
MOCS1 17
MOCS2 19
MOGAT2 6 0 0
MOGS 7
MON1A 6 2
MORC2B 22 2
MORC3 20 17 9
MORC4 22 22.5 18.5
MORF4L2 3
MORN2 19.5 3.5
MOSPD1 11
MOSPD2 12
MOV10 13 17 13
MPDU1 15
MPDZ 19
MPHOSPH6 23
MPI 6 4
MPLKIP 7 11 6
MPP1 3.167
MPP2 21.5 23
MPP4 12
MPP5 23
MPP6 19 21.5 21 20
MPP7 8 7
MPPE1 14
MPPED1 22.5 1 21 2
MPRIP 9 11
MPST 18
MPT 0
MPZL1 7
MPZL2 14
MPZL3 12 23
MR1 1
MRAP 0 4
MRAP2 21
MRAS 2
MRC2 5 18
MRE11A 11
MREG 22
MRGPRA4 2
MRGPRF 7
MRGPRH 4
MRP63 22
MRPL1 7 5.5 8.5
MRPL10 7.5
MRPL14 23
MRPL15 7
MRPL16 8.5
MRPL2 23
MRPL24 7 9
MRPL34 8
MRPL35 11
MRPL36 9
MRPL4 10
MRPL49 18
MRPL50 9 21
MRPL51 23.5
MRPL52 18
MRPS17 19.5
MRPS18B 18
MRPS2 7.5
MRPS21 12 15.5
MRPS22 12
MRPS23 20
MRPS24 10
MRPS27 19
MRPS35 20
MRPS6 21
MRPS7 19 5
MRRF 22
MRVI1 0
MS4A1 19.5
MS4A4C 22
MS4A4D 6 6
MS4A6C 21
MS4A8B 21.5
MSH6 22
MSI2 7 11
MSL1 22 22 21
MSMO1 22
MSN 0
MSRB2 23
MST1R 7.5 9
MSTO1 16
MT1E 17
MT1H 20.5 13 12
MTA1 18 14
MTA2 23 0.5 23
MTA3 18 17 15
MTAP 9 6
MTBP 10
MTCH1 12
MTCP1NB 12.5
MTDH 17 22
MTERFD1 21.5 21
MTFMT 5.5 20 21 21
MTHFD1 12 13
MTHFD1L 13 8.5 8.5 9.5
MTHFR 22
MTM1 19.5 17
MTMR12 8
MTMR14 23.5
MTMR2 5
MTMR4 13.5
MTMR6 16
MTMR9 23.5
MTNR1A 22.5
MTOR 11
MTR 10.5
MTRR 9
MTSS1 12 8 9
MTSS1L 16 18
MTTP 21 23 16 2 0.5 21
MTUS1 9 5 1
MTUS2 2 3 23 19
MTX2 22
MTX3 7
MUC13 22.5
MUC15 13 11
MUC20 4
MUC5B 19
MUL1 1 0 2
MUM1L1 22
MURC 9
MUS81 4
MUSTN1 23.5
MUT 4.5
MUTED 1 6.5
MUTYH 6.5 5 4
MVD 22
MVK 0 3 3 22 2.5
MVP 21
MXD1 0
MXD4 11.5
MXI1 19 19.5
MXRA7 2 23
MYADM 3 11 21
MYADML2 12
MYB 21
MYBBP1A 4.333 5.5 21 4
MYCBP 17
MYCBP2 12
MYD88 11 1.833
MYEF2 9
MYEOV2 15
MYF6 23
MYH10 7 10 7
MYH11 23 7 22
MYH14 6
MYL12A 23
MYL12B 2
MYL4 5.5
MYL6B 23 17
MYL9 21 22 22
MYLIP 8
MYLK 21.5
MYLK4 7 8
MYO10 23
MYO18A 23 12
MYO19 9
MYO1A 8.5
MYO1B 15 9
MYO1C 22
MYO1D 21 21
MYO1E 20 2 21
MYO1G 12 13
MYO1H 7 7
MYO3B 9.5 11
MYO5A 20.5 2
MYO5B 16
MYO5C 22.5 0
MYO7A 16
MYO9B 20 15.5
MYOD1 11
MYOF 23.5
MYOM2 19
MYOT 2 23
MZT1 20 19.5 19 20
N4BP2L1 17 21
N4BP2L2 22 0
N6AMT1 18 22 20 20 18.5 21
N6AMT2 23
NBAS 0
NBEAL2 2 20 19 1
NBL1 21
NBR1 9 11
NCALD 21
NCAM1 22
NCAPD2 21.5
NCBP1 22 2 3
NCBP2 6 8 7
NCCRP1 14 15 11 13 12 16 13
NCDN 17
NCEH1 21
NCK1 20
NCK2 23
NCKAP1 15
NCKAP5 12 12
NCL 7.5 9.5 8 9.5 3
NCOA2 6
NCOA3 20
NCOA5 10
NCOA6 17
NCOA7 23
NCOR2 20
NCSTN 12 12 12
NDE1 20 22 23
NDEL1 15
NDFIP1 16 13.5 18
NDFIP2 22
NDRG1 20
NDRG2 21
NDRG3 5.833
NDST1 20
NDST2 0.5
NDST3 1.167
NDUFA5 0 4.5
NDUFA6 12
NDUFAF4 18 18 17
NDUFB11 9 7 9 12 9
NDUFB3 22
NDUFC1 23
NDUFS2 4
NDUFS6 2
NDUFS7 2
NDUFV1 10
NDUFV3 10 5
NEB 22
NEBL 8 13
NECAB1 2.5
NECAB2 8
NECAP1 6 12.5
NEDD4 0 0 3
NEDD4L 4 2.5 2.5 4
NEDD9 21
NEFM 5.167
NEGR1 12
NEIL1 0 19 0.5
NEK2 12 13
NEK3 0.5
NEK4 11
NEK5 6
NEK7 17
NEK8 4
NEK9 0 20
NELF 6
NELL1 20 15 0
NENF 23
NEO1 19 20 22 22
NET1 10
NETO2 20.5 23 19 20
NEU1 22
NEU2 21
NEU3 21 22
NEU4 9 9 10 15 9 12
NEURL2 11 16.5
NEURL3 23.5
NEURL4 6.5 5
NF1 7
NFAT5 3
NFATC3 14 15 16 20 16.5 16.5
NFATC4 14 14 12.5 14.5 14
NFE2L1 12
NFE2L2 1
NFE2L3 23 2 22.5
NFIA 22.5
NFIB 22
NFIC 13
NFIL3 2.5
NFIX 0 22
NFKB1 14.5 11
NFKBIA 4
NFKBIB 21
NFKBID 23
NFRKB 20.5
NFX1 12 9.5
NFXL1 23
NFYA 21
NGEF 21.5 3 22
NGLY1 12.5
NGRN 14.5 11
NHEJ1 15.5
NHLRC2 5.5 12
NHP2 7 9
NHSL1 4.5
NICN1 20
NID2 9 20.5 19
NIF3L1 2.833
NINJ1 14 13 16
NINJ2 21.5
NINL 22 0 19 17
NIPA1 23
NIPSP1 5 9
NIT2 6 5.5
NKAIN1 6
NKD2 22
NKIRAS1 22
NKIRAS2 18 13
NKTR 0 19.5 0
NKX2-1 23 21.5 0
NLK 6
NLRC5 9.5
NLRP2 21
NLRX1 0
NMBR 21 22.5 17 16 18
NME1 6
NME6 19 21.5 5.5
NME7 19 21 21
NMRAL1 22
NMRK1 3 22.5 10
NMRK2 21 14 5.5
NMT1 9
NMT1 17
NMT2 15
NNT 18 18.5 20.5 15.5 17 21
NOA1 21 0.5 21 18 19.5
NOD2 18.5 21 22 20 21 19 18 21
NOL3 20 20 20.5
NOL4 18.5
NOL6 11
NOL7 19
NOL8 3 0.5 21
NOLC1 21 21 22 21.5 22
NOMO2 20 20.5 22 19.5 19.5 19
NOP16 14
NOP56 22 23
NOS1 22
NOSTRIN 3
NOTCH1 5
NOTCH2 14.5
NOTCH4 7.5
NOX4 4
NOXRED1 3
NPAS2 7 8.5 9 8 12
NPAS3 23 23.5
NPC1 17
NPEPPS 23
NPHP1 10.5
NPHS2 7
NPL 20.5
NPNT 2 17
NPPB 4
NPR2 15 11
NPR3 8
NPRL2 19
NPS 1.5
NPTN 0
NPTX1 5
NPW 23
NPY1R 10
NQO1 23 23.5 16
NQO2 11.5
NR0B2 22.5
NR1D1 19
NR1D2 19.5
NR1H2 16.5
NR1H3 9
NR1I3 7 10
NR2F2 21
NR2F6 21 14.5
NR4A1 0.5
N-R5S162 15 16 13
N-R5S168 20 18
N-R5S176 11 8.5 10
N-R5S2 9 11 6
N-R5S205 19 20 7
N-R5S25 7.5
N-R5S28 18
N-R5S5 0
N-R5S54 18 21 22 20 22
NRADD 3 6 4
NRBP1 20.5
NRBP2 9 9
NRCAM 22
NRD1 7
NREP 23
NRF1 20
NRG4 0 21.5
NRIP1 23
NRP1 5
NRP2 8.5
NRXN1 7
NSDHL 0.5
NSF 20
NSFL1C 3 3 1 4
NSMCE2 6 2 0
NSUN3 8
NSUN6 4.5 22.5 3
NSUN7 9
NT 10
NT5C 20
NT5C1A 12 12 12 13 13.5 12 13 14 12 11 12
NT5C2 9
NT5DC2 8 23
NT5DC3 6
NT5E 6 6
NT5M 4
NTF3 22.5
NTN3 5
NTN4 8.5
NTNG1 7 11.5
NTNG2 7
NTPCR 8 7 20.5
NTRK2 9 11.5
NUAK1 21
NUBP2 16 14 18
NUCKS1 5 4
NUDT1 0
NUDT11 22
NUDT13 18 20 19
NUDT16 11
NUDT17 22
NUDT18 22
NUDT19 20 22 22 22 20.5
NUDT22 3 1 3 2.5 18.5 4
NUDT3 21.5 20 22
NUDT4 21
NUDT5 18
NUDT7 1.5 1 5 4.5 3 19 1
NUDT9 1 2 8 6.5
NUMA1 20
NUMBL 5
NUP205 23
NUP210 13 13
NUP210L 18 18
NUP37 22 0 19
NUP43 19
NUP62 13 12
NUP85 15 20
NUP93 0.5 23
NUP98 4
NUPL1 6
NUPL2 14
NUPR1 8
NUS1 0 2
NUTF2 22
NVL 2 20 22 22
NXF1 5 20
NXN 13 15
NXT2 12
O3FAR1 8
OAF 8 11 16 9
OASL 10 11 14 16 12 12 11 13
OAT 18.5
OAT-RS1 7 8 23 8
OBFC1 21.5
OBFC2A 0.5
OBFC2B 7.5 5.5
OCLN 14
ODC1 22
ODF2 11
ODF3B 21
ODZ1 20
ODZ3 4.5
ODZ4 7
OGFOD1 7
OGFR 15
OGN 17
OGT 19 0 22
OLA1 21
OLFM1 17 2 12
OLFM3 22 2
OLFM4 23 0 6
OLFR10 21
OLFR106-PS 23
OLFR1077-PS1 7 6.5 3.5
OLFR1144-PS1 21
OLFR1167 19 17 19 20 14 20 5.5 21
OLFR1178 11
OLFR121 9
OLFR1261 23
OLFR1307 0
OLFR1314 21
OLFR1342 4
OLFR1346 9
OLFR144 2 7 3 8 5
OLFR1449 1
OLFR1458 7
OLFR22-PS1 6
OLFR295 20.5 14
OLFR332 18.5 16 17
OLFR363-PS 20 1
OLFR367-PS 8
OLFR418-PS1 0.5
OLFR467 9.5 6
OLFR597 16
OLFR702 22.5
OLFR74 9 14
OLFR827 23
OLFR849 20
OLFR855 12.5 13 3 14
OLFR866 8
OLFR883 8
OLFR902 23
OLFR904 13
OLFR907 23.5 20
OLFR913 17 15
OLFR920 2.5
OLFR934 14 23
OLFR967 10 13.5 5.5
OMA1 23 22.5 23.5 17 22.5
OPA3 5
OPALIN 1
OPCML 10.5
OPHN1 17
OPLAH 3
OPN3 22 20.5
OPTN 23
OR10H2 8 6 11
OR10S1 23
OR10X1 19
OR11H4 17
OR12D3 1.5 3 5 21 23 1.5
OR13C8 14.5 22 12.5
OR1L6 9
OR1N1 23
OR2A5 21
OR2B6 22
OR51D1 6.833
OR51Q1 8
OR51S1 20 23 1
OR52D1 8 9.5 11 10 7 10
OR52E6 16 22 16
OR52J3 10
OR56A5 3
OR5M3 4 7 3 4
OR6C65 6.5
OR7A17 3 23.5 4
OR8B8 1
OR9Q2 3 22
ORAI2 23
ORAI3 17 11
ORC3 18 21 17 20 16 20 20
ORC6 12
ORM1 3 9.5
ORMDL2 18
ORMDL3 12
OS9 11.5 9
OSBP2 21
OSBPL10 23
OSBPL11 2.5 4
OSBPL1A 20
OSBPL2 19
OSBPL3 8
OSBPL5 13.5
OSBPL6 6 18
OSBPL7 0
OSBPL8 23 0 0 22 0.5 0
OSBPL9 22
OSGEP 9 9
OSGIN1 3
OSGIN2 13.5
OSMR 15
OSR1 12 13 13
OSTALPHA 3 13 15
OSTM1 10 11 21
OTOP1 6
OTUB2 22 23.5 3 2
OTUD1 19
OTUD5 8
OTUD6B 23 23 3 1.5 3 22 22 1 0
OXA1L 0 1 0
OXCT1 11
OXD1 0 7
OXR1 10 11.5
OXSM 9 20
P1L1 11
P2RX4 18 1
P2RX5 10
P2RX6 15.5 16 14
P2RY1 13 10
P2RY14 1
P2RY2 15
P2RY4 7 7 22
P2RY6 13
P4HA1 2 7.5
P4HA2 12 13
P4HA3 2 4.5
P4HB 21 23
P4HTM 3
PA2G4 19 22
PACS1 9 12.5
PACS2 0
PACSIN2 5.5 4.5
PACSIN3 20
PAFAH1B3 17 16
PAFAH2 5
PAG1 11.5
PAH 1 0.5
PAICS 13 13 12 19
PAIP2B 20 19
PAK1IP1 12.5
PALLD 0.5
PALM 18.5 9
PALM3 19 19 13
PALMD 7 8 9 8 10
PAMR1 13 16
PANK1 22.5
PANK3 4 6
PANK4 17 18
PAPD4 12
PAPD7 9
PAPOLA 10 12.5 15 19
PAPPA 5
PAPSS1 11
PAPSS2 20.5 19 23.5
PAQR3 5.5 7.5 8.5
PAQR4 15
PAQR5 5.5
PAQR7 9
PAQR8 13
PAQR9 18
PARD3 9 12 8.5 9
PARD6G 22
PARK7 8.5
PARL 9
PARM1 8 8 19 8.5
PARP10 22
PARP11 4 6 4
PARP12 19 17
PARP16 10
PARP2 5.5
PARP3 1
PARP8 22
PARVB 17
PATZ1 19 11
PAX8 16
PAXIP1 19 21
PBLD 6
PBRM1 5 0
PBX1 10
PBX3 9.5 9.5 9 11 11
PCBD1 22
PCBP1 5.5 3
PCBP2 7 10.5
PCBP4 10.5
PCCA 14
PCCB 7 8 7
PCDH1 20
PCDH11X 22
PCDH12 2.5 3.5 4 11
PCDH18 4
PCDH7 6 22.5
PCDH9 20
PCDHB11 22
PCDHB6 23
PCDHB7 22 18.5
PCDHB8 7.5
PCGF2 20
PCGF5 21.5
PCIF1 1.5
PCK1 21
PCLO 5
PCMTD2 16.5 22
PCOLCE2 12
PCP4L1 20.5
PCSK1 21
PCSK4 14.5
PCSK6 1
PCSK7 21 1
PCYOX1 5.167
PCYOX1L 21
PCYT1A 21
PCYT2 13.5
PDCD2 8
PDCD4 23
PDCD6IP 23
PDCL 20.5
PDCL3 19
PDDC1 10
PDE1A 12
PDE1B 23
PDE2A 8 0
PDE3A 23
PDE3B 23 10
PDE4A 3.5
PDE4B 23 18 17 18
PDE4DIP 20
PDE5A 21
PDE6D 19
PDE6G 15
PDE7A 4
PDE7B 19
PDE8A 19
PDE8B 0.5
PDE9A 14.5
PDGFA 22
PDGFB 16.5
PDGFC 2
PDGFD 15 16 20.5 15
PDGFRA 3
PDGFRB 23 23
PDGFRL 23.5 23
PDHB 21
PDIA3 5
PDIA4 20.5 22 23
PDIA5 10 21.5
PDIA6 23
PDK2 11 11
PDK4 5.833
PDLIM1 11
PDLIM2 0
PDLIM3 21
PDP1 20
PDP2 7 15
PDPN 9
PDPR 21
PDS5A 7 13
PDS5B 22.5 23
PDXK 10
PDXK-PS 0
PDZD11 1.167
PDZD2 10.5
PDZK1 1
PDZRN3 10.5
PDZRN4 15
PEA15 7.5
PEAR1 18.5 10
PECAM1 6
PEG10 10
PEG3 23
PELI2 9.5
PELP1 10 7 5
PENK 13
PEPD 21
PEPLD 14.5 14.5 17 17
PER1 16 17
PER2 22 22 23
PER3 12
PES1 9
PET112 14
PEX1 22
PEX11A 9
PEX11B 7
PEX14 20 22 23 18.5
PEX16 21
PEX19 10.5 14.5
PEX3 6.5
PEX5 22
PEX7 21
PFDN2 18 16.5
PFDN5 0
PFKFB1 22
PFKFB2 15
PFKFB3 23
PFKFB4 2.167
PFKL 0
PFKM 0
PFKP 21
PFN4 21
PGAP1 19
PGD 6
PGF 7.5
PGLS 12
PGLYRP1 0.5
PGLYRP2 22
PGM1 0
PGM2L1 23.5
PGM3 7
PGM5 23.5
PGP 23
PGPEP1 14
PGR 0.5
PGRMC2 10
PHACTR4 10
PHB2 22 22
PHC3 10.5 21
PHF1 23
PHF15 11
PHF16 21
PHF17 20 19.5
PHF19 11.83
PHF6 22
PHIP 1.167
PHKA1 11 9.5
PHKA2 0.5
PHKG1 23
PHKG2 21
PHLDA1 21.5
PHLDA3 21
PHLDB1 7 6
PHLDB2 4.5
PHLPP1 14.5 16
PHLPP2 23
PHOSPHO2 14 17
PHOX2B 10 14 15 16 14 11.5 12 16 14
PHTF1 7 7.5 12
PHTF2 22
PHYH 17
PHYHIP 16 1
PHYHIPL 18 10
PI15 6
PI16 14
PI4K2A 22
PI4K2B 22 23 11 17 22
PI4KA 22
PIAS2 15.5 14.5
PICALM 22.5 23 0 0
PICK1 13.5
PID1 19 19 22
PIEZO1 11
PIEZO2 22 20
PIGA 7 6
PIGB 14 12 15 13
PIGC 10 6 9 16
PIGH 19.5
PIGL 5.5 9 6.5 11
PIGN 2 21
PIGO 3
PIGR 10.5 5
PIGS 16.5 17 1
PIGT 8
PIGU 3
PIGY 1
PIK3AP1 1 0 1.5 16
PIK3C2G 15
PIK3C3 6.5
PIK3CA 10.5
PIK3IP1 6
PIK3R1 21.5 23
PIK3R2 21
PIK3R3 2 19 23.5
PIK3R6 22
PILRA 22
PIM1 0 19 4
PIM3 22.5
PINK1 0
PION 5.167
PIP4K2A 19
PIP4K2B 21 23 21 18
PIP4K2C 0 22 0
PIP5K1B 2 23
PIPOX 5.5 20
PIR 2 22
PIRT 14
PISD-PS2 22
PITP 21.5
PITPNC1 20.5 22.5
PITPNM1 22.5 23.5
PITPNM2 22
PJA1 21
PKD1 1
PKD2L1 23
PKIA 23
PKLR 21 19 13
PKM 0.5 10
PKMYT1 1.833
PKN1 14 7
PKN2 15 13
PKNOX1 18
PKNOX2 23
PKP2 9 9
PLA1A 3
PLA2G12A 19.5
PLA2G12B 1.5
PLA2G15 23.5
PLA2G4D 18 15
PLA2G5 6
PLA2G7 9
PLA2R1 16
PLAC8 22.5 19.5 15
PLAGL1 5
PLAT 11
PLAU 9 11
PLAUR 2
PLBD1 22
PLBD2 18 12
PLCB1 23
PLCB4 9 9
PLCD3 9 11.5 10
PLCD4 22 22 23
PLCE1 8 0 23.5
PLCG1 21
PLCL1 7
PLCL2 11
PLD1 21
PLD2 20
PLD4 11
PLD6 0 22
PLEC 22 2
PLEKHA1 11
PLEKHA3 11 9 15
PLEKHA6 0.5
PLEKHA8 18.5
PLEKHF1 5
PLEKHG1 8
PLEKHG2 19
PLEKHG3 9 21 13
PLEKHG5 6 23
PLEKHG6 2 1 3
PLEKHH1 23
PLEKHH3 20
PLEKHN1 18.5
PLIN1 20
PLIN2 10
PLIN3 22.5
PLIN4 12
PLIN5 18.5
PLK3 21
PLLP 8
PLN 16 10.5
PLOD1 13.5 16
PLOD2 15
PLOD3 13
PLRG1 1
PLSCR1 13
PLSCR4 21 20
PLTP 20
PLX1 22
PLX2 2 0 2 23.5
PLX4 0
PLXDC1 6.5
PLXDC2 5 8.5 9 3 5
PLXNB1 7 0
PLXNB2 13.5 16 21
PLXNB3 9
PLXNC1 22
PLXND1 21.5 23
PM20D1 20
PM20D2 0 23
PMEPA1 0.5 21.5 22
PML 23 0 23 23
PMM1 10
PMP22 18
PMVK 21.5
PNISR 0.5 15 7
PNKD 11 13 13 12.5 14
PNKP 19 23
PNLDC1 13
PNMAL2 4
PNMT 23
PNP 21
PNPLA1 2 4 22
PNPLA2 22
PNPLA3 4
PNPLA6 15 22
PNPLA7 19 17
PNPO 19 19
PNPT1 12 12.5 20
PNRC1 23
PNRC2 6 7 6 8 10 9 7 6 6
PODN 7 9
PODXL 0 21
POF1B 20
POGLUT1 0
POLA2 7 9 4
POLE 18.5 19 22 21 19.5
POLDIP3 21
POLE3 19
POLE4 9.6667 9.667
POLG 16
POLI 0 23 9 18
POLK 3.5
POLR2A 6 4 6
POLR2B 2
POLR2E 2
POLR2M 14.5
POLR3G 21 12
POLR3GL 23.5
POLR3K 21
POM121 10.5
POMP 23
POMT1 0 21
POMT2 7 8
PON2 17
PON3 21
POP1 23
POP4 23 22
POPDC2 6 9.5
POPDC3 3.5
POR 1.5
PORCN 15 12 13
POT1 22
POU2AF1 5
POU3F3 4.5
POU5F2 19
POU6F1 11.5
PPA1 22 0
PPAP2A 21
PPAP2B 13.5
PPAP2C 19
PPAPDC2 19 20.5
PPAPDC3 20
PPARA 18
PPARD 8
PPARG 6 18.5 19 18 0
PPARGC1A 9.5 12
PPARGC1B 11 9 11 7 13 7
PPAT 1
PPDPF 22 5
PPEF1 19
PPFIA1 2 3.5 3 0 8
PPFIBP1 23 15
PPFIBP2 22 20
PPID 14
PPIF 4.5
PPIG 12
PPIL1 17
PPIL6 2
PPIP5K1 15 15 13
PPIP5K2 17 16 16 13 13 15 14 15 16 14 18
PPL 16.5 17 17 14 18 17 17 19
PPM1A 8
PPM1F 1 14
PPM1H 12 23
PPM1K 15.5
PPM1M 18 16
PPME1 21.5 6 15
PPOX 15
PPP1CB 9.5
PPP1R11 17 12 0 16 18.5
PPP1R12B 21.5
PPP1R14A 17
PPP1R14C 11
PPP1R15B 11 11
PPP1R16B 13
PPP1R18 8 10 6 11
PPP1R21 18 22 20
PPP1R27 8.5 11
PPP1R36 20 20
PPP1R3A 13 13 15 15 14 12 13
PPP1R3B 21 23 19 19 17
PPP1R3C 0
PPP1R3D 13.5
PPP1R7 22
PPP1R9A 7 11 9
PPP2CA 10
PPP2CB 12.5
PPP2R1A 9
PPP2R1B 22
PPP2R2B 23
PPP2R2D 23 19
PPP2R3A 2 19
PPP2R4 6.5 6.5
PPP2R5A 13 16 16 13 15
PPP2R5C 5
PPP2R5D 9 5
PPP3CA 12 22
PPP3CB 14
PPP4R1 22
PPP4R1L-PS 5.167
PPP6R3 21
PPPDE1 4
PPPDE2 2 2.5
PPT1 9 3.5 8
PPTC7 19.5
PPWD1 9
PQBP1 3 3 5 6
PQLC3 23.5
PRAF2 10 0 10.5 9 9
PRAMEF8 13
PRCC 20 1
PRCP 23 14.5
PRDM1 7
PRDM10 11
PRDM2 17 18
PRDM5 22
PRDM6 0 18
PRDX2 22
PRDX3 3
PRDX5 22 23
PRDX6 21.5 4.5
PREB 4.5
PRELP 0 4 23.5 1 0 1
PREP 21 6.5
PREPL 1
PREX1 22 22
PREX2 7
PRG4 22 0
PRHOXNB 12
PRIC285 23 23 22
PRICKLE3 14 9.5 21 1 14
PRIM1 5 21
PRKAA1 23.5
PRKAA2 11.83
PRKAB1 7.5 9 10
PRKACA 2
PRKACB 22
PRKAG3 7
PRKAR1A 16.5
PRKAR1B 13
PRKAR2A 9 15
PRKAR2B 22 0 2 0
PRKCA 1.5
PRKCB 22.5
PRKCD 21
PRKCDBP 21 5
PRKCE 6
PRKCG 8.5
PRKCH 21
PRKCI 23
PRKCQ 11 12 12.5 10
PRKCZ 10 6
PRKD1 13 14
PRKD2 23
PRKD3 21.5 22
PRKG1 8 7 8 7 7 10
PRKG2 6.833
PRL8A1 3
PRLR 23 8
PRM1 5 6
PRMT10 8
PRMT3 23
PRMT8 7
PRND 6
PRNP 0
PRODH 3 1 5 3 3 2 3 3
PRODH2 21
PROM1 19
PRORSD1 9
PROSAPIP1 20 21.5 21
PROSC 2.5 22
PROX1 23
PRPF19 8 12 10
PRPF38B 20 17 22.5
PRPF40A 21
PRPF40B 19.5 22 20.5 21 21
PRPS1 23 0 16
PRPS2 6.5
PRPSAP1 17 0
PRR13 21
PRR14 19 22.5
PRR15 1.167
PRR15L 21.5
PRR16 23.5
PRR5 4.5 0
PRRC1 17
PRRC2C 0
PRRG1 20
PRRG3 14 14 4.5
PRRG4 13
PRRXL1 19.5 17
PRSS23 20.5 23 22
PRSS37 18 23
PRSS8 10 12 11.5 12 12 11
PRT1 21 17 23 21.5
PRTN3 2
PRUNE 3.5 6 23
PRX 22 4 22.5
PSAP 7 8.5
PSAT1 13
PSD3 7.833
PSEN1 19
PSEN2 7
PSG19 11
PSIP1 21
PSMA1 8 11
PSMA6 22.5
PSMA7 10
PSMB3 0.5 21.5
PSMB4 20.5 22 23 0 23 21 23 22
PSMB5 0 0 22 22
PSMB6 16.5
PSMB7 13
PSMB9 23 23
PSMC2 22.5 23
PSMC3 20
PSMC4 18
PSMC6 1
PSMD1 22
PSMD12 9
PSMD13 11
PSMD14 10 15 8
PSMD2 22
PSMD4 23 22
PSMD5 4
PSMD6 17 20 15.5 14
PSMD7 0 0
PSME1 21
PSME2 22 22
PSME4 5 4 7
PSMF1 5
PSTK 2.5 3
PSTPIP2 22 20
PTBP1 3
PTBP2 20 12.5 17
PTCH1 23.5 16 23
PTDSS2 21.5 0
PTER 7.5
PTGDR2 22
PTGDS 22 12
PTGER3 12
PTGER4 23
PTGES 1 10
PTGES3 21 21
PTGFR 5
PTGFRN 20
PTGIS 20 5.5
PTGR1 16 21
PTGS1 21
PTK2 13
PTK6 18 18
PTK7 10
PTOV1 23 19 0.5
PTP4A2 6
PTP4A3 21 0.5
PTPLAD1 0 22
PTPLB 21 22 21
PTPN11 9 11.5
PTPN13 21.5 4
PTPN14 4.5 9
PTPN22 11 11 10.5 12
PTPN3 6
PTPN4 19 19.5 17
PTPN6 7
PTPN9 8 12 19
PTPRB 23 22.5 23 23 22 23
PTPRD 10
PTPRE 6.167
PTPRF 22.5 23.5 21.5
PTPRG 0 0 22
PTPRJ 15 14
PTPRK 10
PTPRM 12 8 11
PTPRS 7 11
PTPRT 4.5 9 23
PTPRU 23
PTPRZ1 9 1
PTRF 22.5
PTRH2 1
PTTG1 6 23 3
PTTG1IP 11.5
PUF60 8
PUS7 14 13.5 16 13 18 13
PUSL1 12.5 14 13 10
PVRL1 2 1 23 23.5 0 1 1.5
PVRL2 6
PWP1 1
PXDC1 23
PXDN 0
PXK 8
PXMP2 16 21 13 16
PXMP4 15 12.5
PYCRL 15.5 23
PYGM 2.5 6 6 6 5 3 4 3
PYGO1 5
PYROXD1 9
QARS 1
QDPR 15 14 15
QKI 4
QPCTL 11.5
QPRT 5.5
QRSL1 2 14
QSOX1 5 3 6 1
QSOX2 3
QTRT1 7 23 10
R3HCC1 15
RAB11FIP3 21 12 22
RAB14 21
RAB15 12 20
RAB17 7 6.833
RAB20 14.5
RAB21 3
RAB22A 1
RAB27B 2
RAB30 22.5 22
RAB31 19
RAB32 7
RAB33A 18.5
RAB34 15.5
RAB35 21 22
RAB39A 23 3 23.5
RAB3A 22
RAB3B 3
RAB3C 0.5 22
RAB3GAP2 6.5
RAB3IP 0
RAB40B 21 22 20 23 17
RAB43 7
RAB4A 8
RAB6A 0
RAB6B 11 22
RAB7A 21.5 15 22 6
RAB7L1 16 18 16
RABAC1 0 22
RABEP1 0 4 0
RABGAP1 12
RABGEF1 20 21
RABGGTA 1 0
RABGGTB 4
RABL2A 14
RABL3 21
RABL5 22
RAC3 9
RACGAP1 9 15 14
RAD18 23
RAD21 10
RAD23B 13 13 18 12.5
RAD50 22.5
RAD51C 19
RAD51D 20 21
RAD9A 14
RAD9B 0 2
RADIL 21 21.5
RAE1 7
RAF1 12.5
RAI1 2
RAI14 19
RALA 14
RALB 22
RALBP1 6.5
RALGAPA2 9 11.5 7 10
RALGAPB 6
RALGPS1 0
RALGPS2 23 22.5 15
RAMP1 16
RAMP2 7
RANBP10 5.5
RANBP17 4 9
RANBP3L 4
RANGAP1 23
RAP1A 23 0 20 23.5 23.5
RAP1B 3 1
RAP1GAP 4 21
RAP2A 23
RAP2C 13 14
RAPGEF1 19
RAPGEF3 7
RAPH1 16.5
RARA 12 12 10.5 9 12 12 11 11
RARB 7.5
RARG 2
RARRES2 9
RASA2 1 4
RASAL2 22 12
RASD1 21
RASD2 1
RASGEF1B 18
RASGRP1 11 8.5
RASGRP3 0
RASGRP4 23
RASIP1 4
RASL10B 10
RASL11A 12
RASL11B 12.5
RASL12 21 15 14.5
RASL2-9 12 19 10.5
RASSF3 13.5
RAVER2 1
RBBP5 13
RBBP9 16
RBCK1 7 10 9.5
RBFA 12 23
RBFOX1 21
RBFOX3 10 11
RBL1 23 5.5
RBL2 10
RBM12B 5.5
RBM22 19
RBM25 4
RBM27 8.5 2
RBM28 12.5
RBM33 12
RBM38 3 23.5 2.5 17 0.5 0
RBM39 2
RBM41 20
RBM42 10 18
RBM45 9
RBM47 18.5 21
RBM4B 17
RBMS1 19
RBMS2 5
RBMX 3 2 8 4
RBP1 12
RBP4 8
RBP7 23
RBPJL 7 6 7 7.5
RBPMS 6
RC3H1 2 0
RCAN1 23 19
RCAN2 22 4
RCAN3 0
RCBTB2 21 18
RCC1 0.5 0 1 0
RCE1 21.5
RCL1 4 21
RCN2 23 14
RCOR1 21 23 0 21 2 22.5
RCOR3 23.5 23
RDH10 23
RDH11 20.5 6
RDH13 22 0 23
RDH5 10 20 12
RDH9 22.5 23 6
RDX 21
RECK 5 1 22.5 22 2
RECQL 5.5 21 10.5
REEP1 19.5
REEP4 6 7
REEP5 22.5 23.5 0 1.5 0
REEP6 7
REL 2 23
RELA 20
RELL1 2.5
RELT 20.5
RENBP 2 10.5
REPIN1 23
REPS1 15 16
RERE 0 23.5 5
RERG 22 23.5 2 1 3
RET 23
RETN 16.5 12
RETNLB 15
RETSAT 7 17
REV1 22
REXO4 8 9
RF 7.5 18
RFC3 11.5
RFC4 8 9 9 7 11
RFESD 0 6 8
RFFL 13
RFK 9.5
RFTN1 7
RFTN2 20 20
RFX3 12.5
RFX4 22 2 2
RFX5 19 14
RFXANK 22.5 14
RG2 19
RGCC 14
RGL1 9.5
RGL3 6
RGMA 19
RGNEF 0 22
RGS12 23 22
RGS16 1
RGS19 3 23.5
RGS2 9
RGS4 6 5
RGS7 20 21
RGS7BP 20 15
RGS9 21.5 1
RHBDD2 16 20.5
RHBDD3 0
RHBDF1 17 15
RHBDF2 2 21
RHBDL3 21
RHOA 12 12
RHOB 0.5 19 21
RHOBTB1 1.5
RHOBTB2 20.5
RHOBTB3 6 6
RHOC 16.5
RHOD 1.5 8
RHOJ 22 0
RHOQ 9 8
RHOU 21 8
RIC8A 18 21 22
RIC8B 13 13 10
RICTOR 4 2.5 3 5
RILP 11.5
RILPL1 22 14 0.5
RIN2 8
RIN3 8.5
RING1 7
RINT1 4 5
RIOK2 16.5
RIPK1 7 0.5
RIPK2 12 12 13 9 12
RIPK3 16
RIPK4 20 20
RIPPLY1 19
RMI1 7
RMND1 15 19.5 20 3.5
RMND5B 13
RND1 18 20 20 19.5 20 22 19 18
RND2 18
RND3 0 20 23
RNF11 9
RNF114 13
RNF115 4
RNF122 6
RNF125 8 13 11 8
RNF135 7.5
RNF14 2
RNF141 11
RNF144A 21
RNF144B 6
RNF145 7.167
RNF146 0 1 0
RNF149 19
RNF150 21
RNF152 21
RNF167 20
RNF168 21 21 20 23
RNF169 17
RNF181 0 0
RNF183 12
RNF19B 5
RNF2 19 23
RNF207 6 7.5
RNF208 3 22 2 23
RNF213 11 6 4
RNF214 7
RNF215 16 17 20
RNF220 19 18.5 18
RNF24 3
RNF32 17 16 13
RNF34 0
RNF39 20
RNF4 6
RNF40 17
RNF43 9.5 20
RNF8 8
RNFT1 13 11.5 13 15
RNFT2 22
RNGTT 21 20.5 22.5 22.5 20
RNH1 16 23
RNPEP 21.5
ROBO1 11.5
ROBO4 1 22
ROGDI 19 19
ROMO1 21.5 4.5 22
ROPN1L 12
ROR1 22
RORA 23
RORC 13 23
RP24-221A14.2 23 0 0 2 1.5 23 23 23.5 23 23
RP9 23
RPA1 0 0 23
RPAIN 21 10
RPE 6 7 7.5
RPF1 16.5 13
RPGR 11
RPH3AL 21 21
RPL15-PS1 22 15
RPL23 9.5 12 9
RPL24 11
RPL7L1 16
RPLP1 6 6.5
RPN1 11
RPN2 10.5
RPP21 17
RPP25 3.5 23 1
RPP25L 6.5
RPP30 22.5
RPP38 10
RPRD1A 1.5
RPRD1B 19
RPS11 22.5
RPS14 20.5 21
RPS15A 8.5
RPS19 23 1 2.5 2 1
RPS3 18
RPS6KA1 23
RPS6KA3 23
RPS6KA4 21.5
RPS6KB2 12.5
RPS6KC1 22
RQCD1 17
RRAGC 14
RRAGD 7
RRAS 18
RRAS2 22.5
RRBP1 16
RREB1 22 8
RRM2 10.5 10.5 6 14 14.5
RRP12 5.5
RRP1B 1 1
RRP8 20 10
RRP9 15 21 20 12
RS 2 4.5
RS2 7 4
RSAD1 23 6.5
RSAD2 15 3
RSBN1 1 23
RSBN1L 13.5
RSE_MRP 7
RSE4 13
RSEH2B 21.5
RSEP_NUC 5
RSPO3 19
RSPRY1 18.5 23 19 21
RTDR1 5.5 18
RTEL1 22.5 19 21.5
RTKN 11
RTN4IP1 19 21 23 1.5
RTP1 14
RTP3 15
RTTN 0
RUFY2 8 18 11
RUFY3 12
RUFY4 7
RUNDC3B 20
RUNX1 23.5 6
RUNX1T1 21.5
RUSC2 19 18 20 0 0 20.5
RUVBL1 1
RWDD1 8.5
RWDD3 16.5
RWDD4 10.5
RXFP4 1
RXRA 10
RXRB 4
RXRG 22
RYK 19.5 20 21
RYR3 20 19
S100A1 22
S100A10 0
S100A16 19.5
S100A4 0.167
S100A9 3
S100B 8
S100G 5
S1PR1 19
S1PR3 15.5
S1PR4 19 19
S1PR5 17 19
SACS 17 18
SAE1 20.5 21 21
SAFB2 5.5 20 21 18.5 18
SAMD12 13 13 11 17
SAMD4A 17 15
SAMD5 5.5 8
SAMD8 17
SAMD9L 3
SAMM50 7
SAP30L 1
SAR1A 6 2 11.5
SAR1B 4 23
SARS 10
SASH1 5
SAT1 18.5 17
SBDS 6
SBF1 9
SBF2 2
SBK1 3.5
SBNO2 8
SC5DL 0
SCAF1 12
SCAF11 0
SCAMP1 3.5 3
SCAMP2 21.5
SCAMP3 0
SCAP 23.5
SCAPER 9
SCARB1 22 22 22
SCARB2 18.5 18.5
SCD 6 11.5
SCD2 2 3 23
SCD3 6.5
SCD4 0.5 23 23 21 22 0
SCEL 5.833
SCFD1 14 2 22
SCGB1A1 4
SCGN 16 6 23 22.5
SCIN 2.5
SCLT1 6
SCLY 4.5
SCN1B 6
SCN2A 15 16.5 18 18 16.5
SCN2B 23
SCN3A 8
SCN3B 7 10
SCN7A 21
SCNM1-PS 12 11
SCNN1A 3.5
SCNN1B 9 8 8.5
SCO1 20.5
SCP2 10 23
SCPEP1 22
SCRN1 8 2
SCRN3 15 8 9.5 15 12 13.5 9 20
SCTR 8 9 13.5 0.5
SCXA 4.5 18.5
SCYL1 20
SDC1 22
SDC2 23 1 4 11
SDC4 3.5
SDCCAG8 19 9
SDF2 22.5 3.5
SDF2L1 21
SDHAF1 9 22 22
SDHD 8.5 23.5 12.5
SDK2 3.5
SDPR 4
SDR16C5 9.5
SDR42E1 1
SDR9C7 1.167
SEC13 21 3
SEC14L1 22
SEC14L2 10
SEC14L4 23.5
SEC14L5 10.5 12 11
SEC16B 4
SEC22B 9.5
SEC23A 9 10
SEC23B 6.5 9
SEC24A 9.5
SEC24B 23
SEC24C 23.5
SEC31A 23 0
SEC61A1 21
SEC62 10.5
SEC63 22.5
SECISBP2L 14
SECTM1 23 0 20
SEL1L 23 21
SEL1L3 20
SELE 12
SELENBP1 5.5 7 22 22 2
SELENBP1 1 22
SELL 7 9
SELM 10 9 9
SELO 3 19
SELRC1 10 8
SEMA3B 19.5
SEMA3G 8
SEMA4A 13
SEMA4B 13
SEMA4C 12
SEMA4D 21 22
SEMA5A 12 13
SEMA6A 9
SEMA6B 18 19.5
SEMA6D 20 9.5
SEMA7A 11
SENP2 13
SENP3 16
SENP6 6
SEPHS2 19
SEPSECS 8
SEPW1 4 6.167
SERAC1 0 0
SERBP1 13
SERF1B 9 4.5 11
SERINC2 8
SERINC3 6
SERINC5 4 3.5 3 3
SERP1 2 6.5
SERPI3B 8
SERPI3C 19.5 19.5 16
SERPI3F 9 10.5 11 11 11 10.5 10 10 10 10 10 11
SERPI3M 23 2
SERPI5 10 10 2
SERPI6 16
SERPI7 8.5
SERPINB1 22
SERPINB12 1 0 23 23 22 23 0 23
SERPINB6B 21
SERPINB9 6
SERPINE1 1 22
SERPINE2 15
SERPINF1 1
SERPINF2 19
SERPINH1 12 13
SERPINI1 13 10
SERTAD2 5
SERTAD4 22 21
SESN1 21
SESN2 21
SESN3 22
SET 8 6
SETD1B 4 2
SETD7 22
SETD8 0
SEZ6 18
SF1 4.167
SF3A2 10 21 4
SF3B1 18
SF3B3 6
SFN 6.5 8 9
SFPQ 5.5
SFRP4 0 23
SFRP5 13 14 15 12.5 14 14 12 16
SFSWAP 0 5
SFT2D2 1
SFTPB 14
SFXN1 10.5
SFXN5 23 0 1.5
SGCD 22
SGCE 19 5.5 18.5
SGK1 1
SGK110 13 5
SGK196 18 14
SGK2 18.5
SGK3 23.5 23.5 22
SGMS1 21 20 6.5
SGMS2 9
SGOL2 13 11
SGPL1 5
SGPP1 11.5
SGPP2 11
SGSH 23
SGSM3 0
SGTA 14
SGTB 19 19 21 14 4
SH2B2 16
SH2B3 7
SH2D3C 20
SH2D4A 22
SH3BGRL2 17 18
SH3BGRL3 18
SH3BP5 19
SH3D19 12 11 9.5 10 10.5
SH3D21 20 4
SH3GL2 16
SH3KBP1 11.5 15
SH3PXD2A 23
SH3PXD2B 19
SH3RF2 6
SH3TC2 23
SHANK2 23 23 0 22.5 23
SHANK3 17 20 21
SHARPIN 13 12 11
SHB 2 23
SHC3 23.5
SHC4 18.5
SHCBP1 20 19
SHISA2 20
SHISA4 5.5
SHISA6 22
SHKBP1 2.5 21
SHMT1 2
SHMT2 13
SHOC2 22.5
SHPRH 20 14.5 5 7
SHROOM2 23 21 9
SI3 3
SIDT1 23
SIDT2 8
SIGIRR 14
SIGLEC1 13
SIGLEC10 21.5
SIGMAR1 8
SIK1 9.5 8
SIK2 22.5
SIKE1 3
SIL1 22
SIPA1 9.5
SIPA1L1 21 1
SIPA1L2 5.5 9 10
SIPA1L3 3
SIRPA 17
SIRT1 13
SIRT3 23
SIRT4 6
SIX1 5
SIX4 16
SKA2 11 15
SKI 2
SKIL 0 0
SKIV2L 7
SKIV2L2 22 7
SKP2 14 21
SLAIN2 20.5 1.5
SLC10A2 14 13.5 13 11
SLC10A5 21.5
SLC10A6 12.5
SLC11A2 9
SLC12A2 6 1
SLC12A4 22
SLC12A7 11.5
SLC12A9 21
SLC13A1 22 20 1
SLC13A2 22 5.5
SLC13A3 9.5 11
SLC13A4 7 5
SLC15A1 17
SLC15A3 11
SLC15A4 3 3.5
SLC16A1 5
SLC16A10 8 11.5
SLC16A11 5.167 7 8
SLC16A12 15
SLC16A13 6.5 6
SLC16A14 14
SLC16A2 19
SLC16A4 16 14
SLC16A5 20
SLC16A6 7.5
SLC16A7 0
SLC16A9 23
SLC17A3 2
SLC17A4 4
SLC17A5 23
SLC17A8 3
SLC17A9 21
SLC18B1 5
SLC19A1 0 6
SLC19A2 6
SLC19A3 0
SLC1A1 6 7 13
SLC1A2 23 23.5 5 19 23.5
SLC1A3 21.5 21 22
SLC1A4 11.5 12.5 12 13 12 13 11 10
SLC1A5 17 5.5 19 18 18 19.5 17 19 19
SLC20A1 23 2
SLC20A2 8
SLC22A10 13
SLC22A15 22
SLC22A17 20 7 3
SLC22A2 6
SLC22A22 21 22
SLC22A23 14
SLC22A3 19 13.5
SLC22A4 12 23
SLC22A5 12 14.5 8.5
SLC22A6 23
SLC22A8 21 18 23.5 20.5 17 19
SLC23A1 22.5
SLC23A2 17
SLC24A3 13
SLC24A4 12 5.5
SLC24A6 4.5
SLC25A1 1.5
SLC25A10 22 0 1 0 1 2 2
SLC25A11 18.5 18.5 18.5
SLC25A15 7.167
SLC25A16 9 12 19.5
SLC25A18 5
SLC25A19 21
SLC25A20 13
SLC25A21 7 8 9 10 6.5 7
SLC25A22 11
SLC25A25 21
SLC25A26 6 23.5 23
SLC25A27 7 7 8
SLC25A28 18
SLC25A30 12
SLC25A32 8
SLC25A33 10
SLC25A34 23
SLC25A35 3
SLC25A36 9
SLC25A37 8
SLC25A38 21 23.5 23
SLC25A39 11
SLC25A40 20
SLC25A42 10 10 7.5 11 1 10
SLC25A44 20
SLC25A46 23
SLC25A47 7.833
SLC26A1 23.5 1 2 3
SLC26A10 21.5
SLC26A11 12.5
SLC26A2 11
SLC26A4 17
SLC26A6 8.5
SLC26A9 23 1
SLC27A1 23
SLC27A2 22.5
SLC27A6 22.5
SLC28A1 21
SLC28A2 7
SLC29A1 11 12
SLC29A3 10 11 8 12
SLC2A1 5
SLC2A12 15
SLC2A13 21
SLC2A2 23
SLC2A3 22
SLC2A5 10 11 11.5 11 10 11 11 9 13
SLC2A8 9.5 9.5 11 6
SLC2A9 22
SLC30A1 23
SLC30A10 21
SLC30A2 12 12
SLC30A6 23.5
SLC31A1 20 21
SLC31A2 3
SLC33A1 18 18.5
SLC34A2 11
SLC35A1 0 0.5 22
SLC35A5 23.5
SLC35B1 23
SLC35B2 12
SLC35B4 9 8
SLC35C1 2.5 2
SLC35C2 0 5
SLC35D1 12 21
SLC35D2 19
SLC35E1 1.5
SLC35E2B 2
SLC35F3 0
SLC35F5 21 2 23 1.5
SLC35G1 0
SLC36A1 22
SLC36A2 22 3
SLC37A1 23
SLC37A2 3 3 3 3
SLC37A4 1 2 2 2.5
SLC38A1 23.5 4 2
SLC38A2 14 15.5
SLC38A3 6 4
SLC38A4 2 4
SLC38A6 4 1 3.5 6 3.5
SLC38A7 1
SLC38A9 18 20.5 15
SLC39A10 23
SLC39A11 22
SLC39A14 16.5 9 12
SLC39A2 22 11
SLC39A4 12
SLC39A8 21.5 22
SLC39A9 5.833
SLC3A2 17
SLC40A1 8 9.5 15 16 17 5.5 14 13
SLC41A1 21.5
SLC41A2 21.5 20
SLC41A3 2
SLC43A1 9 10
SLC43A2 0.5
SLC43A3 7
SLC44A1 23.5
SLC44A2 22.5
SLC44A3 19
SLC44A4 5.5 23
SLC44A5 17
SLC45A1 11
SLC45A3 0
SLC46A3 8 8
SLC47A1 8
SLC4A11 22
SLC4A2 1
SLC4A4 13 21
SLC4A7 12
SLC4A8 22
SLC50A1 7.5
SLC52A2 4
SLC5A12 2
SLC5A3 0 0 2 23 0 2 0 0 2
SLC5A6 9.5
SLC5A8 12.5 4 2.5
SLC6A13 0 2.5 21 0.5 22
SLC6A14 11 15 19 14.5
SLC6A15 17
SLC6A17 14.5
SLC6A18 23 13
SLC6A19 20 21
SLC6A20 5 10 2
SLC6A4 20 21 5.5 23 23
SLC6A6 21
SLC6A8 22
SLC6A9 22
SLC7A10 19 15
SLC7A11 21
SLC7A2 10
SLC7A5 22
SLC7A6 23 2 2.5 6 23 23 22
SLC7A8 10 19.5
SLC7A9 22
SLC8A1 21
SLC9A1 22 0 1 2 0 22 23 23 1 23.5
SLC9A2 23
SLC9A3 12 9 10
SLC9A3R1 18 20 16 3.167
SLC9A3R2 11.5
SLC9A9 23.5 2 2 1.5
SLCO1A6 8.5 10
SLCO1B3 21.5
SLCO2A1 11.5
SLCO2B1 23.5 23
SLCO3A1 14 13
SLCO5A1 13
SLFN1 14.5
SLFN13 3 21 22
SLFN5 21
SLIT1 23 20.5 22
SLIT2 20
SLIT3 5 7
SLMAP 2
SLMO2 6
SLN 2 1 2 23.5 0 0 23.5 1
SLPI 1
SLTM 11
SLU7 12
SMAD1 11
SMAD3 0.5
SMAD6 2 2 2 15.5 0 23 10
SMAD9 13
SMAGP 21.5 22
SMAP1 21.5 19
SMAP2 18
SMARCA2 7.5 9 10.5
SMARCA4 17
SMARCAD1 4.5
SMARCAL1 20.5
SMARCB1 21 23 1
SMARCC1 23 2
SMARCC2 22 22.5
SMARCD1 0.5
SMARCD2 13 3 23
SMARCD3 11
SMC5 6
SMCHD1 6 5 10 10 10 6 4
SMCP 5
SMCR7 12.5 15 17
SMCR8 12 9
SMG1 18
SMG5 11
SMO 15
SMOC1 18
SMOK2A 23
SMPD1 18.5
SMPD2 6 6.5 4.5
SMPD3 9.5 11
SMPD4 10.5
SMPDL3A 21
SMPDL3B 9
SMT3H2-PS2 6
SMTN 8 23 21.5
SMTNL2 6.5 8 7.5 8.5
SMURF2 16
SMYD1 21 18
SMYD2 14 12
SMYD5 17 19 14.5
SNCA 20 21
SNCG 23
SND1 12 9
SNF8 8
SNHG11 21 5.5 21 22
SNORA21 6 21.5
SNORA22 22 23
SNORA23 21
SNORA32 0
SNORA38 5.5 20.5
SNORA42 21 13 9 9
SNORA54 14 4.5
SNORA55 3.5 4
SNORA61 2
SNORA70 20
SNORA71 12 14
SNORA72 4.5
SNORA73 21
SNORA74A 6
SNORA7A 21.5
SNORA9 13
SNORD104 16 13 16
SNORD113 6.5 23
SNORD15A 23 21
SNORD35B 13
SNRK 23
SNRNP200 7.5
SNRNP27 17 0
SNRNP40 11
SNRNP48 3
SNRNP70 12
SNRPB 7
SNRPB2 11
SNRPD2 16 17 18 15
SNRPD3 15.5
SNRPG 12.5 12
SNTA1 6 9
SNTB1 6.5
SNTB2 1
SNTG2 23.5 0.5 1
SNUPN 21 21 1 20 1
SNW1 11
SNX12 9
SNX14 0
SNX16 12
SNX17 12
SNX18 21 21
SNX21 10 14
SNX22 20
SNX27 0
SNX29 5.5
SNX3 21 22
SNX30 0 0
SNX31 16
SNX32 23
SNX33 23
SNX6 0
SNX7 9 5
SNX8 2.5
SOAT1 8.5
SOBP 17
SOCS2 6
SOCS7 22.5
SOD1 9
SOD2 5 6
SOGA1 6.833
SOGA3 8 8 11 11
SORBS1 19
SORBS2 0
SORBS3 10
SORCS2 21 19
SORCS3 5.167
SORD 6.5
SORL1 17
SORT1 13 15
SOS2 8 6 12
SOSTDC1 22.5 0.5 19
SOWAHB 0
SOX12 0
SOX17 0 14
SOX18 16.5 22
SOX4 4.5 5 2.5
SOX6 12 5.5 22.5
SOX7 8
SOX9 22
SP1 5.5
SP100 18
SP23 23.5 22 22 19 22 23 22 22 23
SP25 17 14
SP3 22
SP4 2 7
SP47 21.5 22 1 21.5 23
SP91 7.5 8
SPA17 9
SPAG1 8.5
SPAG6 13 3 8
SPAM1 8 9
SPARC 23 2
SPATA13 7 8 8
SPATA17 19
SPATA22 22
SPATA24 6
SPATA5 6.5
SPATS2 12 11.5 14 13
SPC24 2.5 23 23.5
SPC3 22.5 21 2
SPCS2 12
SPCS3 20
SPECC1 11
SPEF2 20
SPEN 4
SPG20 6
SPG21 0 9
SPHK1 6
SPHK2 23
SPIB 9
SPIC 15 14.5 16
SPICE1 15 14.5
SPINK5 23 1 1.5
SPINT1 22
SPIRE1 22
SPN 4
SPNS2 21
SPOCK2 0
SPON1 15 15 10
SPON2 8 23
SPOP 10 8.5 13 13 12
SPP1 21
SPPL2A 9 20
SPPL2B 20 17
SPPL3 3
SPRED1 1
SPRED2 15
SPRR1A 21
SPRR2A3 8 8 8.5
SPRY1 21 6 3 21
SPRY2 3
SPRYD3 7 1 14
SPRYD4 9.5
SPRYD7 22.5 5.5
SPSB1 11 21.5
SPSB3 6
SPSB4 0 1 23.5 3 0
SPTA1 22
SPTAN1 20.5
SPTB 7 9 8 7
SPTLC1 23
SPTLC2 5.5 3
SPTSSB 21
SQLE 4
SQSTM1 10
SRBD1 9
SRD5A1 13 0
SRD5A2 23.5
SREBF1 4
SREBF2 6
SREK1 2 23.5
SREK1IP1 2
SRF 23
SRGAP1 21 19 0
SRGAP2 7 6.5
SRGAP3 23 1
SRGN 22 7.5
SRM 1.5
SRMS 5.5
SRP72 11 9 12
SRPK1 3.5
SRPK2 1
SRR 9
SRRD 5
SRRM1 5.5
SRRM2 23
SRRT 5.5
SRSF1 4
SRSF10 16 15 16.5 17 15
SRSF2 8.5
SRSF3 4
SRSF6 10
SRXN1 2
SS18 14 12.5
SS18L1 11.5 23 13.5
SS18L2 17 18
SSBP2 18 0 19
SSBP3 20 20.5 17
SSBP4 21 20.5
SSFA2 18
SSPN 9 10
SSR1 13 13 11.5
SSR4 11.5 1 21 2
SSX2IP 13
ST13 5
ST3GAL1 5.5
ST3GAL3 13
ST3GAL4 9
ST3GAL5 21
ST3GAL6 21 23
ST5 1
ST6GAL1 22 23 22.5 23
ST6GALC2 22
ST6GALC3 19.5
ST6GALC5 10
ST6GALC6 11.5
ST7 12 7.5
ST7L 23 23.5
ST8SIA1 23.5
STAB1 6.167
STAG1 12
STAM 10 9.5 11 10 9
STAM2 22
STAMBP 6
STAP1 15
STAR 0
STARD13 11 5
STARD3NL 14 13 20.5 17 13
STARD4 6
STARD5 17
STAT2 9
STAT3 12
STAT4 22 21
STAT5A 7
STAT5B 23 22 22
STBD1 23 1.5
STC1 9
STC2 4.5 2
STEAP2 11
STEAP3 16 12
STEAP4 6 5
STIM2 23.5
STIP1 8
STK10 20.5
STK11 10.5
STK16 1
STK17B 7
STK24 21
STK25 20
STK32A 1
STK32B 12 3.5 23
STK32C 6.5
STK35 10 22
STK36 23
STK38 7
STK39 21
STK4 7
STK40 19
STMN2 22
STOM 7 7.5
STON2 12
STOX2 1
STRA13 21.5 10 22.5
STRAP 13 14 11.5 11 9
STRBP 17 18.5 16.5
STRN 4
STRN4 20
STT3A 17
STT3B 6.5 9
STX11 23 17 21 17
STX16 23
STX17 23
STX18 23 3.5 2.5
STX1B 11
STX2 5.5
STX3 6
STX4 6.5
STX5 23
STX7 20
STXBP1 22
STXBP2 16.5 0
STXBP4 4.833
STXBP5L 20.5 9.5
STXBP6 7
SUCNR1 0
SUDS3 22.5 3.5
SUFU 0 1
SUGP1 5 5 9
SULF1 22
SULF2 0
SULT1A3 10
SULT1C2 23 1 21
SUMF2 3
SUMO3 5
SUN2 7 9 11.5 12
SUOX 9 9 11
SUPT16H 9
SUPT4H1 22
SUPT7L 10
SUSD1 21 4 3 6 4
SUSD3 21 22 22.5 21 23 18
SUSD4 14
SUV420H1 20
SVEP1 1 23 16
SVIL 22 23
SVS6 23 21
SWSAP1 3
SYAP1 21
SYDE2 7
SYK 10
SYN2 23
SYNC 14
SYNE2 3
SYNJ2 21.5
SYNM 10 8.5
SYNRG 18 13
SYPL1 9
SYPL2 0
SYS1 3.5 23
SYT1 2
SYT11 3.5 23
SYT12 22 22 21 23 22 22.5 23 22 0
SYT14 17
SYT15 11
SYT17 7
SYT2 23.5 21 22
SYT3 1 23 1 2
SYTL2 23
SYTL5 12 7 5
SYVN1 5.5
SZT2 20
T10 7.5
T6 15
T8 5.5
T8L 18 21 21 20 18.5 5.5 20
TAAR7F 22
TAB2 6 2.833
TAB3 12
TACC1 20
TACC2 17 9
TACO1 20 22 8
TACR1 15
TADA2B 22
TADA3 6 1.5
TAF1 13 4.5
TAF11 15 13 5 9 21
TAF15 8 6.5
TAF1B 4.5 22
TAF2 21
TAF4 11
TAF4B 7
TAF6 1
TAF6L 18
TAF9B 18.5
TAGAP 21
TAGLN 17 11 23
TAGLN2 20
TAMM41 1.5
TANC2 13.5 12.5
TANK 4
TAOK2 19
TAOK3 15 16 18 15.5 14 15
TAP1 12.5
TAPBPL 0
TAPT1 17
TARBP1 3
TARDBP 20 8 22
TARS 21
TARS2 10.5 9 22
TAS2R14 22
TAS2R143 5.5 15.5
TAS2R4 20 20.5
TASP1 5.5
TATDN1 5
TATDN2 4 10
TATDN3 7.5
TBC1D1 7 9 5.5 5
TBC1D10A 19 17
TBC1D10C 5.5
TBC1D13 23.5
TBC1D14 12
TBC1D15 22 0
TBC1D16 9
TBC1D17 22
TBC1D20 8.5 9
TBC1D22A 20 17 17
TBC1D22B 3.5
TBC1D24 22 3
TBC1D25 20.5
TBC1D2B 11
TBC1D4 8 4
TBC1D5 18.5 14
TBC1D7 1.5
TBC1D8 1
TBC1D8B 16
TBC1D9 7.5 8.5
TBCD 3
TBCE 21 22.5
TBCEL 19
TBCK 1 22
TBL1X 11 22
TBL2 21 12
TBL3 22
TBRG4 21
TBX10 22 21.5
TBX5 15 21
TBXAS1 21 17
TCAP 6 2
TCEAL1 22
TCEAL8 5.5
TCEB1 10 5
TCEB2 21
TCF19 19 21.5
TCF20 22.5
TCF25 21
TCF4 1
TCF7L2 18.5
TCHHL1 11
TCIRG1 17
TCN2 1
TCOF1 9
TCP1 14
TCP11L2 22
TCTA 11
TCTEX1D2 1
TCTEX1D4 21.5
TCTN2 4
TDO2 1 0
TDRD3 5 23
TDRD5 23
TDRD6 1
TDRKH 8.5
TEAD1 16 16 1
TEAD4 12
TECPR1 19 5.5 17
TECPR2 18 21
TECR 10 11.5
TEF 6
TEK 12 12
TEKT5 21
TENC1 19
TERF1 23
TERF2IP 5 3
TES 5.5 14
TESK2 22
TET2 23
TET3 19
TEX11 2
TEX12 22 21
TEX2 21
TEX261 0
TEX264 7
TEX9 10.5 19
TFAP2B 21
TFB1M 22
TFCP2 20 19
TFCP2L1 10
TFDP2 0 5.5
TFE3 13.5 10
TFEB 17
TFEC 12 7
TFPI 6
TFPI2 10 11 11 10 12 11 10 10 11 9 10.5
TFPT 23.5
TFR2 7
TFRC 16.5
TG 21
TGFA 23
TGFB3 4 15
TGFBI 1 22 3 7
TGFBR1 5
TGFBR2 23
TGFBR3 21
TGIF1 23
TGM1 8
TGM2 21
TGOLN2 13
THADA 23
THAP1 1 0
THAP2 20.5
THBD 22
THBS1 20 22
THBS2 0
THEM4 23
THEM5 22
THOC3 22
THOC5 10
THOC6 2.5
THPO 23
THRA 0
THRAP3 6
THRB 22
THRSP 8 9 8.5
THSD4 14
THTPA 21 22 5.5
THYN1 16.5 6
TIA1 21
TIAM1 7.5 8
TIE1 21.5
TIFA 14.5
TIG 17
TIGL1 8 13 7.5 9
TIMD2 22
TIMD4 8
TIMM10 12.5
TIMM8B 11
TIMM9 20
TIMMDC1 21 13
TIMP2 5
TIMP3 3
TIMP4 8 12 7 9
TINF2 6 1 1.5
TIPARP 5 0
TIPIN 8.5 21
TIRAP 18
TJP2 22
TJP3 18.5 10.5 15.5
TK1 23 5 3 2
TK2 22.5
TLCD1 9 21
TLCD2 17
TLE1 19
TLE3 3
TLE4 6 7 7 10 8
TLK1 10
TLL1 2.5
TLN1 21
TLN2 1
TLR2 21 22
TLR3 9 21
TLR6 23.5
TM2D2 22.5 21
TM4SF1 17
TM4SF4 23
TM6SF2 0.5 22.5
TM9SF1 9.5
TM9SF3 18 14
TMC1 16 16
TMC6 7
TMC7 7 22
TMCC2 21 22.5
TMCO1 13
TMCO3 21.5
TMCO4 23 5.5
TMCO6 2 21 1.5
TMED5 22
TMED6 23
TMED8 21 6
TMEFF1 18
TMEFF2 6
TMEM100 21 18.5
TMEM102 23
TMEM106A 1.5
TMEM106B 21 12
TMEM107 2.5
TMEM108 18.5
TMEM109 22.5
TMEM11 7
TMEM111 8
TMEM115 12
TMEM117 11
TMEM120A 5.5
TMEM120B 19
TMEM123 10.5
TMEM127 21
TMEM129 21
TMEM131 3
TMEM132B 2
TMEM132D 20.5
TMEM135 14 12
TMEM140 12 9 7 7 5
TMEM141 15 17
TMEM144 22
TMEM145 20
TMEM147 0.5 23 0 22
TMEM14A 11.5 2
TMEM14C 10
TMEM150A 22.5
TMEM159 6 0.167
TMEM160 9
TMEM164 15
TMEM167A 4
TMEM170A 21 10
TMEM170B 1
TMEM171 5 3
TMEM173 23
TMEM174 23
TMEM175 9.5
TMEM176A 14 13.5
TMEM176B 21 22
TMEM177 22.5
TMEM178 4 7
TMEM179B 23
TMEM180 8 11 10
TMEM182 22
TMEM184A 2.5
TMEM184B 9 8.5 8.5
TMEM184C 12 12
TMEM185A 10 13
TMEM19 8
TMEM192 9.5
TMEM194A 3
TMEM196 22 17 21
TMEM198B 15.5
TMEM200B 3.5
TMEM204 8
TMEM205 4.5 2
TMEM207 12 13
TMEM209 22.5
TMEM212 19.5
TMEM214 21
TMEM216 23
TMEM218 13 17 4
TMEM220 4
TMEM229B 13 14
TMEM234 15
TMEM236 0
TMEM237 21 16.5
TMEM242 21 8
TMEM245 12
TMEM25 12
TMEM26 22.5
TMEM27 23
TMEM33 23.5
TMEM35 22
TMEM37 23
TMEM38B 23 12
TMEM39A 22
TMEM39B 9 9 9.5 11 10 11 11 9 10 8 9
TMEM41B 11 8.5 14.5 11 7
TMEM42 9
TMEM45A 9
TMEM47 9.5 9
TMEM50A 8.5
TMEM50B 0.5
TMEM55A 7 8
TMEM55B 22.5 21
TMEM56 22
TMEM57 19.5 0
TMEM62 6
TMEM63B 16
TMEM63C 14
TMEM64 9
TMEM67 9.5 8
TMEM68 0.5 22.5
TMEM71 21
TMEM80 13
TMEM85 0
TMEM86A 14
TMEM86B 0 23
TMEM87A 15.5 13
TMEM8A 1 6 4.5 1.5
TMEM9 17
TMEM98 13
TMEM9B 23
TMIE 8 9.5
TMOD1 21
TMPO 7 9.5 9
TMPRSS11A 22
TMPRSS13 19
TMPRSS5 8 8 10
TMTC1 12 0
TMTC2 8
TMX1 5
TMX3 18
TNC 5
TNFAIP1 10 11
TNFAIP2 21.5
TNFAIP3 4.167
TNFAIP8 19.5 21
TNFAIP8L1 23
TNFRSF12A 22.5 7
TNFRSF19 18 22
TNFRSF1B 2.5 4
TNFRSF21 0
TNFRSF22 5
TNFSF10 23
TNFSF12- 20
TNFSF13B 21 3.5 22
TNFSF15 22 19.5
TNIK 22.5
TNIP1 21
TNK2 18 21
TNKS1BP1 10 10
TNNC1 9
TNNI1 15 19 18 16
TNPO1 23
TNPO2 2.833
TNR 0.5
TNRC6B 4.833
TNS1 18
TNXB 0 5 23
TOB2 23
TOMM20L 21 16
TOMM34 22 0 13 20
TOMM40 9
TOMM7 8 9
TOP1 6
TOP1MT 19
TOP2B 4
TOP3B 9 8.5
TOR1A 22 12 4
TOR1AIP1 21
TOR1AIP2 21
TOR1B 12
TOR2A 22.5
TOR3A 17
TOX 3.5 23.5
TOX2 13 10
TP53 8
TP53BP1 18
TP53BP2 23
TP53I11 5 23.5 23
TP53INP1 8 9
TP53INP2 13
TPCN1 6
TPD52L2 13
TPGS2 3 0
TPK1 23 23
TPM1 1.5 1 3
TPMT 22
TPP1 5.5 18.5
TPPP 23
TPPP2 5.167
TPPP3 22 21
TPRA1 12 22
TPSAB1 14.5
TPST1 19
TPST2 14
TRA2A 20
TRABD 21 23 23 22.5
TRAF3 12 9
TRAF5 3
TRAFD1 15
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TRAK2 7
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TRAM2 22.5
TRAPPC1 10
TRAPPC12 14
TRAPPC2L 8 8
TRAPPC3 19 7 22.5 22 23
TRAPPC8 16.5 16 17 5 21.5 13
TRAPPC9 20.5
TRDMT1 8
TRDN 0 6.5 23 1
TRERF1 11
TRIB1 6 21
TRIB3 22.5
TRIL 22
TRIM12A 12
TRIM13 21
TRIM14 21
TRIM16 22
TRIM2 19 19 18 5.5 16
TRIM23 6
TRIM24 21
TRIM25 2 1
TRIM3 8.5
TRIM30B 11 13.5
TRIM37 2.5
TRIM40 15
TRIM41 23
TRIM44 19
TRIM5 9
TRIM56 4 7.5
TRIM6 8
TRIM63 16 14
TRIM65 4
TRIM68 23
TRIM7 22
TRIM8 22
TRIM9 22
TRIP10 21
TRIP12 21 9 19 16
TRIP4 13 3.5 20 12
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TRMT5 10.5 22
TRMT6 21 23
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TRPM3 12 11
TRPM7 7 8 14 11 11
TRPS1 7 14 9.5
TRPV4 9
TRRAP 23 23
TRU1AP 8
TSC1 23
TSC22D1 14 14.5
TSC22D3 6
TSGA10 21 16 14 15
TSHR 7.5
TSHZ3 8
TSKU 6
TSLP 17
TSPAN1 9 6
TSPAN11 2
TSPAN13 20.5 19
TSPAN14 6.5 7 6
TSPAN17 22
TSPAN18 12
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TSPAN33 20 13 15.5
TSPAN4 0
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TSPAN6 23
TSPAN7 23
TSPAN9 8.5 9
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TSPYL5 1 4 23 0
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TTC26 23
TTC28 8.5 17
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TTC39C 5
TTC4 21.5 0
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TTC9 21 23.5 22
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TTLL5 20
TTLL7 18
TTLL8 15.5
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TTYH3 18
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41700 22.5
41703 23
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Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.
The following examples further illustrate aspects of the present invention. However, they are in no way a limitation of the teachings or disclosure of the present invention as set forth herein.
EXAMPLES The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only and the invention should in no way be construed as being limited to these Examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.
Methods and Materials: Animal Preparation and Organ Collection Mice were prepared as previously described (Hughes, et al., 2009, PLoS Genet., 5:e1000442). Briefly, 6-week old male C57/BL6 mice were acquired from Jackson Labs, entrained to a 12 h:12 h light:dark schedule for one week, then released into constant darkness. Starting at CT18 post-release, three mice were sacrificed in the darkness every 2 h, for 48 hours. Specimens from the following organs were quickly excised and snap-frozen in liquid nitrogen: aorta, adrenal gland, brainstem, brown fat (anterior dorsum adipose), cerebellum, heart, hypothalamus, kidney, liver, lung, skeletal muscle (gastrocnemius) and white fat (epididymal adipose). Food and water were supplied ad libidum at all stages prior to sacrifice. All procedures were approved by the Institutional Animal Care and Use Committee.
Microarray Data Organ samples were homogenized in Invitrogen Trizol reagent using a Qiagen Tissuelyser. RNA was extracted using Qiagen RNeasy columns as per manufacturer's protocol, then pooled from three mice for each organ and time point. The reason for pooling was to average out both biological variance between individual animals and technical variance between individual dissections. RNA abundances were quantified using Affymetrix MoGene 1.0 ST arrays and normalized using Affymetrix Expression Console software (RMA). Probesets on the Affymetrix MoGene 1.0 ST array were cross-referenced to best-matching gene symbols using Ensembl BioMart software, then filtered for known protein-coding status. The resulting 19,788 genes formed the protein-coding background set.
RNA-Sequencing Data RNA samples from CT22, CT28, CT34, CT40, CT46, CT52, CT58, and CT64 were pooled for each organ, as described above (96 total pools). These RNA pools were converted into Illumina sequencing libraries using Illumina TruSeq Stranded mRNA HT Sample Preparation Kits as per manufacturer's protocol. Briefly, 1 μg of total RNA was polyA-selected, fragmented by metal-ion hydrolysis, and converted into double-stranded cDNA using Invitrogen Superscript II. The cDNA fragments were subjected to end-repair, adenylation, ligation of Illumina sequencing adapters, and PCR amplification. Libraries were pooled into groups of six and sequenced in one Illumina HiSeq 2000 lane using the 100 bp paired-end chemistry (16 lanes total). Details on alignment and quantification are included in the Supplementary Methods.
Oscillation Detection The JTK CYCLE (Hughes et al., J. Biol. Rhythms., 25:372-80) package for R was used, with parameters set to fit time-series data to exactly 24 h periodic waveforms. Significance was bounded by q<0.05 for array data sampled at 2 h and by p<0.05 for sequencing data sampled at 6 h.
Quantifying and Aligning RNA-Sequencing Data Fastq files containing raw RNA-seq reads were aligned to the mouse genome (mm9/NCBI37) using STAR (Dobin et al., 2013, Bioinforma. Oxf. Engl., 29:15-211) (default parameters). RNA-seq quantification was performed using HTSeq®, run in stranded mode (default parameters). Protein-coding genes were quantified using the Ensembl annotation (Flicek et al., 2012, Nucleic. Acids Res., 40:D84-903). Non-coding RNAs were quantified using data from the NONCODE v3 database (Bu et al., 2012, Nucleic. Acids Res., 40:D210-2154). Quantification values were normalized using DESeq2 (Anders et al., Genome Biol., 11:R1065).
Identifying Non-Coding RNAs Conserved Between Humans and Mice This study began by downloading BED files listing ncRNA coordinates for humans and mice from the NONCODE v3 database. These bed files contained 33,801 human and 36,991 mouse transcripts. To prevent overlapping ncRNAs from confounding the analysis (many of these appeared to be alternative spliceforms of the same ncRNAs), all overlapping ncRNAs were merged on the same strand using the BEDTools suite (Quinlan et al., Bioinforma. Oxf. Engl., 26:841-842). This merge step resulted to 20,042 human and 27,286 mouse transcripts. By the coordinates for these merged transcripts and the UCSC Genome Browser (Meyer et al., 2013, Nucleic Acids Res., 41:D64-69), the nucleotide sequences was downloaded corresponding to each of these ncRNAs in FASTA format. Next, separate human and mouse BLAST libraries were constructed from these ncRNA sequences by running the make blastdb command with default parameters. Following this, BLAST (Altschul et al., 1990, J. Mol. Biol., 215:403-4108) was used to align the mouse ncRNA sequences against the human ncRNA BLAST library, and vice-versa. Since ncRNAs have previously been shown to have relaxed constraints on sequence conservation (Washietl et al., 2014, Genome Res., 24:616-28), blastn was run using the more permissive dc-megablast algorithm and a minimum e-value cutoff of 1E-10. These BLAST results for pairs of human and mouse ncRNAs that were each other's top BLAST hit (termed “reciprocal best hits”) were mined. Filtering for these reciprocal best hits left with 1601 human and mouse transcript pairs, termed conserved ncRNAs. Conserved ncRNAs using these relaxed BLAST parameters were found well-known, conserved ncRNAs like Xist, Tsix, Hotair, H19, and Gas5.
To assign names and annotation data to these conserved ncRNAs, BLAST was used to align their sequences to human and mouse RefSeq (Pruitt et al., 2009, Nucleic Acids Res., 37:D32-3610) transcripts. 585 of these conserved ncRNAs were mapped to protein-coding genes (i.e. RefSeq IDs beginning with NM or XM) in the sense orientation in both humans and mice. Upon visual inspection of these ncRNAs, it was found that many of these mapped along the entire length of the protein-coding transcripts. While some ncRNAs in this list might represent non-coding isoforms of these protein-coding transcripts, they were removed from further analysis as a result of conservative approach. Following the removal of these transcripts, a final list of 1016 conserved ncRNAs were left. Biotypes (defined by GENCODE (Harrow et al., 2012, Genome Res., 22:1760-177411) and Ensembl) were assigned to these transcripts using both Ensembl and manual annotation. Quantification and analysis of these transcripts was performed like all other RNA-seq transcript data.
Identifying Novel ncRNAs
Given that RNA-seq data is not limited to a specific gene annotation, novel transcripts were sought to be characterized. The study began by collecting all reads that mapped across splice junctions (i.e. reads with large gaps in their alignments). Reads falling into this class were identified by STAR during alignment and stored in files having with the SJ.out.tab extension. While this caused missing single-exon transcripts, the data came from a real, expressed transcripts if evidence of RNA splicing was found. To reduce the impact of spurious reads and noise, splice junctions were mapped by a minimum of 16 reads across entire dataset (this corresponds to 2 reads per time point in a single organ). A fairly low threshold was chosen so as not to remove junctions present in only a single organ, and those circadian transcripts expressed in a bursting patterns (like Dbp). Next, the BEDTools was used to filter out any junction mapping within 1 KB of any Ensembl or Refseq transcript, or overlapping with any NONCODE transcript. All of these steps left with 10,452 junctions from putative transcripts. All junctions within 500 bp of each other were merged to form 5,154 putative, ncRNA transcript regions. These putative transcripts were quantified and analyzed like all other RNA-seq transcripts.
Disease-Genes, Drug Targets, and Other Data Sources Disease-gene annotations were aggregated from the following sources: Online Mendelian Inheritance in Man (Hamosh et al., Nucleic Acids Res., 33:D514-712), Universal Protein Resource (Update on activities at the Universal Protein Resource (UniProt) in 2013, Nucleic Acids Res., 41:D43-7), Comparative Toxicogenomics Database (Davis et al., 2013, Nucleic Acids Res., 41:D1104-1414), Pharmacogenomics KnowledgeBase (Whirl-Carrillo et al., 2012, Clin. Pharmacol. Ther., 92:414-715), Literature-Derived Human Gene-Disease Network (Bundschus et al., BMC Bioinformatics, 9:207). Drug target genes were pulled from the DrugBank database (Law et al., 2014, Nucleic Acids Res., 42:D1091-109717). List of WHO essential medicines downloaded from WHO website (http://www.who.int/medicines/publications/essentialmedicines/en/, 10/10/2014). MicroRNA target predictions for PTGS1 from TargetScan (Lewis et al., 2005, Cell, 120:15-20).
Tissue culture and cell maintenance. NIH3T3 cells were purchased from ATCC. These cells were maintained in growth media containing 10% FBS (Atlanta Biologicals), 1× Penicillin/Streptomycin/Glutamine (Gibco), and 1× Non-essential amino acids (NEAA; Gibco) in Dulbecco's Modified Eagle's medium (DMEM; Gibco). Cells were grown in a humidified incubator at 37° C. and 5% CO2.
Transfections All transfections were performed in the forward format. Briefly, cells were seeded in 6-well dishes at a density of 2.5×105 cells/well, in media containing no antibiotics (DMEM, 10% FBS, 1× Glutamine (Gibco), 1×NEAA). Cells were incubated overnight at 37° C. and 5% CO2. On the following day, cells were transfected using Opti-MEM (Gibco) and the RNAiMAX (Invitrogen) reagent, according to manufacturer's protocol. Cells were transfected with mirVana Negative Control #1, mmu-miR-22-3p mimic, or mmu-miR-22-5p mimic (Life Technologies), at a final concentration of 50 nM. Transfected cells were incubated for 72 hrs at 37° C. and 5% CO2. RNA and protein were harvested from the same well by collecting cells in ice-cold PBS, and dividing these cells suspensions into two aliquots. For each well, one aliquot was processed for protein, and the other was processed for RNA.
Western Blot Whole-cell protein extracts were isolated from cells using ice-cold RIPA buffer (Sigma), supplemented with Complete protease inhibitor cocktail (Roche). Protein concentrations were quantified using the DC protein assay (BioRad). 4 μg of protein was resolved on 7.5% polyacrylamide, Tris-HCL/Glycine/SDS gels (BioRad) and transferred to PVDF membranes. Membranes were blocked for 1 hr at room temperature in blocking solution (5% milk, 0.05% Tween20, 1× Tris-buffer saline), followed by overnight incubation at 4° C. with primary antibody in blocking solution. Primary antibodies used were: anti-PTGS1 (160110; Cayman Chemical), and anti-GAPDH (sc-25778; Santa Cruz). Membranes were then rinsed twice each with TBS-0.05% tween and blocking solution. Following rinses, membranes were probed with secondary antibody at room temperature for 70 min. Those membranes treated with anti-PTGS1 were incubated with anti-mouse IgG HPR-linked secondary antibodies (NA931V; GE Healthcare), while membranes treated with anti-GAPDH were incubated with anti-rabbit IgG HPR-linked secondary antibodies (NA934-1ML; GE Healthcare). Membranes were then rinsed 5 times for 10 min in TBS-0.05% tween, and then imaged using standard autoradiograph techniques after the application of Western Lightning Plus ECL (PerkinElmer) western blotting detection reagent.
RNA Extraction and Quantitative PCR RNA was extracted from cells using TRIzol reagent (Life Technologies) with Direct-zol RNA MiniPrep kit (Zymo research), according to manufacturer's protocol, cDNA was generated from 500 ng of RNA using the qScript cDNA Synthesis Kit (Quanta Biosciences) and qPCR was performed on the ViiA 7 Real Time PCR System (Life Technologies) using the PerfeCTa FastMix II, Low ROX reagent (Quanta Biosciences), according to the manufacturer's protocols. Relative expression quantification of the qPCR data was performed using the ΔΔCT method with the ViiA 7 analysis software v1.2 (Life Technologies). Ptgs1 (Mm00477214_ml; Life Technologies) was quantified using Gapdh (4352661; Life Technologies) as the endogenous reference.
Example 1: Genes and Non-Coding Transcripts A background set of 19,788 known protein-coding mouse genes was defined and for each organ the JTK CYCLE (Hughes et al., 2010, J. Biol. Rhythms., 25:372-8011) algorithm to detect 24-hour oscillations in transcript abundance was used. For this protein-coding gene analysis, the high temporal resolution of the array data was leveraged to accurately identify circadian genes. A 5% false discovery-rate was set for detection, though the specific value of this cutoff did not affect the relative amount of rhythmic transcripts detected between organs (FIG. 5, Panel A). The base-pair level RNA-seq data was used in a complimentary fashion to identify the expressed spliceforms of these circadian genes, and for analysis of the non-coding transcriptome.
Following these analyses, it was found that liver had the most circadian genes (3,186), while hypothalamus had the fewest (642) (FIG. 1, Panel A). In fact, the three brain regions (cerebellum, brainstem and hypothalamus) had the fewest circadian genes, collectively. Due to the technical difficulty of precisely sampling brain regions, it was assumed that heterogeneous mixtures of cell types within these complex organs may express different sets of genes, or may be out of phase with each other. This transcript/phase-discrepancy within the same organ would make it difficult to accurately identify circadian genes in these brain regions. On average, 46% (s.d.=0.036%) of circadian protein-coding genes expressed multiple spliceforms detected in the RNA-seq data.
Transcript abundance for 43% of protein-coding genes oscillated in at least one organ (FIG. 1, Panel B). Only ten genes oscillated in all organs: Arnt1, Dbp, Nrld1, Nr1d2, Per1, Per2 and Per3 (core clock factors), as well as Usp2, Tsc22d3, and Tspan4. While the organs analyzed provide a broad sampling across the entire organism, there are still many more to study which may contain additional circadian genes. The average number of total circadian genes, y, detected by randomly sampling x organs was closely modeled by the exponential function y=a(1-ebx), where e is Euler's number and the coefficients a (asymptote) and b (rate of asymptotic approach) equal 10,901 and 0.123, respectively (R2>0.99; FIG. 1, Panel C). This estimate remains unchanged if we exclude the potentially noisy, heterogeneous tissues discussed above (FIG. 5, Panel B). In other words, as additional organs are sampled, without bounding to a specific theory, it is predicted that ˜10,901 mouse protein-coding genes (55% of the background set) will show circadian oscillations somewhere in the body.
To study the non-coding transcriptome, the NONCODE was used to define a background set of 1,016 mouse-human conserved ncRNAs (FIG. 6, Panel A). It was found 32% of conserved ncRNAs oscillated (a similar proportion compared to protein-coding genes), while non-conserved ncRNAs were less likely to oscillate (FIG. 1, Panel D). This suggests the set of conserved ncRNAs may be functionally relevant. Unlike protein coding genes, no individual ncRNA oscillated in more than five organs. This is unsurprising, given that ncRNA expression is known to be organ-specific (Washietl et al., 2014, Genome Res., 24:616-28). It was also found 712 of 5,154 unannotated, spliced non-coding transcripts had rhythmic expression. 80% of these aligned to the human genome (BLASTN, E<10−10, sequence identity>70%), indicating they are conserved between human and mouse.
These conserved, clock-regulated ncRNAs covered a diverse set of functional classes (FIG. 6, Panel B). 30 of them were antisense to protein-coding genes, half of which were themselves circadian. There was no general phase relationship between sense and antisense ncRNAs. For example, in the liver, both Galt (galactose-1-phosphate uridylyltransferase) and an overlapping antisense ncRNA oscillated in phase with each other (FIG. 7, Panels A-D). Host genes for 39 circadian miRNAs and four snoRNA host genes were identified: Cbwd1, Snhg7, Snhg11, and Snhg12. As snoRNAs were recently shown to have light-driven oscillations in Drosophilabrains (Hughes et al., 2012, Genome Res., 22:1266-1281), these findings provide further evidence of the clock's potential to influence ribosome biogenesis (Jouffe et al., 2013, PLoS Biol., 11:e100145515). It was also found 74 conserved lincRNAs with circadian oscillations, the majority of which were Riken transcripts with no known function. Finally, it was also found 1979 genes with un-annotated antisense transcripts, 187 of which showed sense and antisense oscillations in the same organ. Of these, 43 antisense transcripts oscillated at least eight hours out of phase with their sense transcripts. Genes with antiphase, antisense oscillators included Arnt1 and Per2 (FIG. 7, Panels E-H). A known Per2 antisense transcript (Koike et al., 2012, Science 338:349-3549; Vollmers et al., 2012, Cell Metab., 16:833-845) oscillated in 4 organs, the most of any antisense transcript, providing further evidence of its functional relevance. Taken together, the data reflect a vast and diverse set of transcripts regulated by the clock at the organism level.
Data regarding circadian oscillations, including coding and non-coding genes, are available via the World Wide Web (www) bioinf.itmat.upenn.edu/circa, a subset of which is summarized in Table 2, supra.
Example 2: Gene Parameters The finding from previous multi-organ studies agreed with the data generated above that the vast majority of circadian gene expression is organ-specific (Panda et al., 2002, Cell, 109:307-20: Storch et al., 2002, Nature, 417:78-837), with little overlap of circadian-gene identity between organs (FIG. 2, Panel A). In most organs, expression of circadian genes peaked in the hours preceding subjective dusk or dawn, often in a bi-modal fashion. Heart and lung were notable exceptions, with phase distributions that diverged substantially from other organs. Moreover, those circadian genes expression peaks clustered around subjective dusk or dawn also tended to have the highest average oscillation amplitude, compared to genes with expression peaks at other times of day. Taken together, these data suggest that the body may experience daily “rush hours” of transcription at these critical times. Using the average phase difference between any two organs' shared circadian genes as a distance metric, an ontogenic tree that recovered recognizable organ lineage was constructed (FIG. 2, Panel B) (Edgar et al., 2013, PloS One 8:e66629). Thus, developmentally related organs tended to share genes that oscillate synchronously. Having examined their oscillation patterns, genomic characteristics common to rhythmically-expressed genes was analyzed. Circadian genes clustered physically in the genome (FIG. 2, Panel C). Their lengths tended to be longer than non-rhythmic genes (Mann-Whitney U test p<<10−15; FIG. 2, Panel D). This trend was maintained at the level of 5′UTR, CDS, and 3′UTR (FIG. 8, Panels A-C). These results are in agreement with previous findings about oscillating liver transcripts (Wu et al., 2012, PloS One, 7:e46961). By using gapped, junction-spanning reads to discriminate between expressed spliceforms, it was found that circadian genes had more spliceforms than non-circadian genes (Mann-Whitney U test p<<10-15; FIG. 8, Panels D-F). Furthermore, it was found that the spliceforms expressed by circadian genes, including the identity of the dominant spliceform, tended to differ across organs more than for non-circadian genes. These findings are consistent with the idea that the circadian genes have more regulatory capacity than noncircadian genes. Remarkably, 1,400 genes were phase-shifted with respect to themselves by at least six hours between two organs, with 131 genes completely anti-phased (FIG. 2, Panel E). For example, at dusk, the transcript levels of Vegfa (vascular endothelial growth factor) peaked in brown fat but reached a nadir in heart. Such drastic phase-discrepancies of individual genes between organs have not been reported. The mechanisms for these phenomena are unclear, as the genes did not share any obvious transcription-factor or miRNA-binding motifs. The core clock genes oscillated synchronously, with the peak phases of a given gene falling within 3 hours of each other across all organs (FIG. 9). Several core clock genes did show 1-2 hour phase advances and delays in skeletal muscle and cerebellum, respectively, when compared to other organs. However, these cases were in the minority, and given the limitations in our ability to precisely resolve small (<2 hour) phase differences from data with a 2-hour resolution, their significance remains unclear. This finding indicates that the anti-phased patterns observed in genes like Vegfa are not due to phase-differences between the core clocks of each organ. Rather, these phenomena are due to additional, organ-specific levels of timing regulation positioned between the core clock and these output genes.
Example 3: Pathways Given the high temporal and spatial resolution of the study, ways in which time and space influenced biological pathways was examined. The Reactome database (Matthews et al., 2009, Nucleic Acids Res., 37:D619-2218) was used as a basis for pathway network and found many pathways enriched for circadian genes both within and across organs (FIG. 10). Several genes oscillated synchronously across all organs, like the core clock genes. For example, Dtx4, a Notch pathway E3 ubiquitin ligase, oscillated in phase with Arnt1 in all organs (FIG. 3, Panel A). It was also noted that genes with “opposite” functions (e.g., activators vs. repressors) often had opposite phases. For example, members of the initial vascular endothelial growth factor (VEGF) signaling cascade oscillated in the heart (FIG. 3, Panel B). These included the primary circulating ligand, Vegfa, and its two principle membrane-bound receptors, Flt1 and Kdr. This cascade regulates angiogenesis, with critical roles in development, cancer and diabetes (Folkman et al., 2007, Nat. Rev. Drug Discov., 6:273-86). At dusk, expression of Vegfa and Kdr in the heart was low, while Flt1 was high. KDR is thought to mediate most of the known cellular responses to VEGF-signaling, while FLT1 is thought to be a decoy receptor (Zygmunt et al., 2011, Dev. Cell, 21:301-1420). Thus, the rhythmic timing of these receptors appears to reflect function, in that FLT1 (the decoy) is present when KDR is not and vice versa.
While members of some systemic pathways, such as the core circadian clock, were expressed in phase across organs, many were not. For instance, expression of the insulin-like growth factor Igf1 oscillated in the liver, peaking in the early subjective night (FIG. 3, Panel C). Since the liver produces nearly all of the circulating IGF1 (Sjögren et al., 1999, Proc. Natl. Acad. Sci. USA, 96:7088-92), IGF-signaling throughout the entire body is likely under clock influence. IGF1 is one of the most potent natural activators of the PIK3-AKT-MTOR pathway, which stimulates growth, inhibits apoptosis, and has a well-known role in cancer (Franke et al., 2008, Oncogene, 27:6473-6488). However, peak expression of Pik3r1, which encodes the regulatory subunit for PIK3, did not occur at the same time across all organs. Instead, there was a steady progression throughout the night spanning nearly ten hours, as it peaked first in liver, then heart, followed by aorta, lung, skeletal muscle, and finally in kidney (FIG. 3, Panel C). Since the core clocks of these organs were in phase with each other, as mentioned earlier, the timing differences of Pik3r1 are most likely driven by some unknown, organ-specific mechanism situated between the core clock pathway and Pik3r1. Some pathways known to function systemically were only rhythmic in a single organ. For example, IGF1's principal membrane-bound receptor, IGF1R, is present in numerous tissues. However, Igf1r expression oscillated only in kidney. In addition to Igf1r, many other membrane-bound receptors that activate the PIK3-AKT-MTOR cascade were also rhythmically expressed only in kidney (FIG. 3, Panel D). These included Erbb2, Erbb3, and Erbb4 (tyrosine kinase receptors), T1r2 (toll-like receptor), Cd19 (antigen receptor), and I17r (cytokine/interleukin receptor). These receptors were all notably in phase with one another, all having peak expression in the subjective mid-day. Thus, there is kidney-specific clock regulation of PIK3-AKT-MTOR signaling, that is distinct from and in addition to the already clock-regulated IGF1 signal coming from the liver.
Example 4: Drug Targets and Disease Timing is an important but underappreciated factor in drug efficacy. For example, short half-life statins work best when taken before bedtime, as cholesterol synthesis peaks when we sleep (Miettinen et al., J. Lipid. Res., 23:466-7323). The relationship between a target for a marketed drug and a circadian gene was examined. Notably, 56 of the top 100 best-selling drugs in the United States, including all top seven, target the product of a circadian gene (Table 1). Nearly half of these drugs have half-lives less than 6 hours (Table 1), suggesting the potential impact time-of-administration could have on their action. Most of these drugs are not dosed with consideration for body time and circadian rhythms. Furthermore, 119 of the World Health Organization's list of essential medicines target a circadian gene, including many of the most common and well known targets (Table 2). For example, Ptgs1 (cyclooxygenase-1, alias Cox1), the primary target of low dose aspirin therapy used in secondary prevention of heart attacks (Antithrombotic Trialists' Collaboration, 2002, BMJ, 324:71-8624), oscillated in the heart, lung, and kidney (FIG. 4, Panel B). Given that aspirin has a short half-life and that heart attacks have a circadian rhythm (Curtis et al., 2006, Ann. Med., 38:552-9.2), dosing aspirin at an optimal time of the day has great potential. Consistent with this observation, clinical reports have suggested night-time administration of low dose aspirin may be important for its cardio-protective effects (Hermida et al., 2005, Hypertension, 46:1060-8). The data suggest a mechanism for Ptgs1's circadian regulation as well. Mir22 is a micro-RNA predicted to target PTGS1, and its host transcript oscillated anti-phase to Ptgs1 in the heart, lung, and kidney. This miRNA may therefore regulate Ptgs1 function. To test this hypothesis, mir22 mimics were transfected into NIH3T3 cells and knocked down endogenous quantities of PTGS1 protein by 50% (FIG. 11). A slight, non-significant decrease was observed in Ptgs1 mRNA levels in these same samples. These data suggest that mir22 operates on PTGS1 predominantly at the posttranscriptional level, though it remains possible that Ptgs1 is a transcriptional target of the clock through other mechanisms. Beyond drug targets, circadian genes were also enriched among disease-associated genes (Pearson's Chi-square test, p<<10−15; FIG. 4, Panel A), and were highly studied in biomedical research. They received significantly more PubMed citations than non-oscillating genes (Mann-Whitney U test, p<<10−15; FIG. 4, Panel C). Furthermore, oscillating genes were also associated with nearly every major disease funded by National Institutes of Health at significantly higher rates than expected by chance (FIG. 4, Panel D). Cancer, diabetes mellitus type 2, Alzheimer's disease, schizophrenia, Down's syndrome, obesity, and coronary artery disease were most strongly associated with circadian genes. For example, many of these oscillating genes are involved in neurodegeneration, including Fus, Tdp43, alpha synuclein, gamma synuclein, Atxn1, Atxn2, Atxn3, Atxn7, Atxn10, Psen1, and Psen2. These genes are mutated in frontotemporal dementia, ALS, Parkinson's disease, spinocerebellar ataxia, and Alzheimer's disease. They were predominantly rhythmic outside of the brain in peripheral tissues (Psen2 had nearly four-fold amplitude in liver and peaked at subjective day, when mice are going to sleep). Without bounding to a specific theory, it was speculated that promoters for these genes may have evolved sensitivity to global changes in redox state, which varies between day and night (Musiek, et al., 2013, J. Clin. Invest., 123:5389-400). Lending credence to the association between clocks and neurodegeneration are two clinical observations: many patients with neurodegeneration-linked dementia display ‘sundowning’ (behavioral problems in the early evening), and most patients with neurodegeneration eventually develop circadian sleep disorders (Hastings et al., 2013, Curr. Opin. Neurobiol., 23:880-73).
Example 5: Methods for Designing a Formulation This example generally describes methods for designing a formulation for treating one or more diseases, conditions, or disorders associated with genes that are expressed with circadian rhythms (i.e., genes that oscillate with circadian rhythm). The formulation has regulated release of at least one therapeutic compound such that the compound's release coincides with peak or trough expression of one or more of the compound's target genes and in at least one tissue type.
Initially, a disorder, as well as the therapeutic compounds capable of treating the disorder, are identified. Examples of both disorders and therapeutic compounds are listed in Table 1, supra. Next, target gene(s) for the therapeutic compounds are ascertained. Examples of target gene(s) for various therapeutic compounds are also listed in Table 1. Likewise, the half-lives of exemplary therapeutic compounds are listed in Table 1.
Next, circadian oscillations in transcript expression (including peak expression) for the target genes in specific tissue types are determined. Data regarding circadian oscillations, including coding and non-coding genes, are available via the World Wide Web (www) bioinf.itmat.upenn.edu/circa, a subset of which is summarized in Table 2, supra.
Using the information provided in Tables 1 and 2 as well as known methods well known in the art for making appropriate immediate release and/or time-releases formulations (see, e.g., “Remington: The Science and Practice of Pharmacy” 22nd edition, Allen, Loyd V., Jr. editor, Pharmaceutical Press, Hampshire, UK (2012), which is herein incorporated by reference in its entirety), suitable formulation(s) can be devised that will be useful in treating disease(s), condition(s), or disorder(s) associated with genes that are expressed with circadian rhythms.
When a therapeutic compound has one target gene in one tissue, the formulation is designed so that release (after ingestion of the formulation) of the therapeutic compound coincides with peak or trough expression of the target gene in the target tissue. Consideration of the compound's half-life can also be made such that the compound's release period and plasma levels coincide with expression period of the target gene. For example, once release has begun, a release period may be greatly-extended for a compound having a short half-life so that the compound's activity persists. On the other hand, once release has begun, a release period for the compound may be immediate or shortly-extended for a compound having a long half-life.
Likewise, consideration of the target gene's expression period can be made when designing the formulation to ensure coincidental release of the compound with a substantial fraction of the gene's expression. For example, if a target gene is expressed over a long period, then a release period of the compound (once release has begun) could be extended. On the other hand, a release period of the compound (once release has begun) may be immediate or shortly-extended for a target gene with a short expression period.
In some cases, it may be advantageous for the formulation to release the compound in two (or more) portions such that formulation is designed to initially release a first portion of the compound and later release a second portion. This would be advantageous, for example, when the compound has a short half-life and/or the target gene has a long expression period.
A given therapeutic compound may have more than one target gene in one tissue. If the expression periods of the more than one target genes do not precisely coincide, it may be necessary to design a formulation to release the compound in two (or more) portions, with a first portion acting upon the earlier-expressed target gene and a second portion acting at the later-expressed target gene such that the formulation is designed to release a first portion of the compound before releasing a second portion. Again, as described above, consideration of the compound's half-life and/or the lengths of the target genes' expression periods can be made when designing such formulation(s).
Other therapeutic compounds may have a target gene that is differentially expressed in more than one tissue type. If the expression of the target gene do not precisely coincide between tissue types, it may be necessary to design the formulation to release the compound in two (or more) portions, with a first portion acting at the tissue type having earlier-expression of the target gene and a second portion acting at the tissue type having the later-expressed target gene. Here, the formulation is designed to release a first portion of the compound prior to releasing a second portion. Again, as described above, consideration of the compound's half-life and/or the lengths of the target genes' expression periods can be made when designing such formulation(s).
Some therapeutic compound(s) may have two (or more) target genes that are differentially expressed in more than one tissue type. If the expression periods of the target genes do not precisely coincide between tissue types, it may be necessary to design the formulation to release the compound in two (or more) portions, with a first portion affecting the target gene having earlier-expression and a second portion affecting the later-expressed target gene such that the formulation is designed to release a first portion of the compound before releasing a second portion. Again, as described above, consideration of the compound's half-life and/or the lengths of the target genes' expression periods can be made when designing such formulation(s).
Additionally, formulation(s) may be designed to include more than one therapeutic compound. The more than one therapeutic compound may have two (or more) target genes that are differently expressed, in time and/or in tissue types, such that it may be necessary to design the formulation to release the compounds sequentially with a first-released compound affecting the earlier-expressed target gene and a second-released compound affecting the later-expressed target gene. Again, as described above, consideration of the compounds' half-lives and/or the lengths of the target genes' expression periods can be made when designing such formulation(s).
Formulations may also be designed such that one therapeutic compound is released coincidental with peak or trough expression of its target gene and a second therapeutic compound is released at times that may be independent of its target gene's peak or trough expression. In such formulations, the second therapeutic compound may have effects (intended or side effects) that can be minimized by controlling the time of the compound's release. For example, a compound that has a stimulatory effect should be released when a subject is awake rather than when the subject is trying to sleep, and a compound that has a diuretic activity should likewise be released when a subject is awake. On the other hand, a compound that is soporific should not be released with the subject is awake. Additionally, release of one or more compounds may be delayed to avoid activity of an enzyme that metabolizes one or more of the compounds.
Formulations can also be designed including more than two (e.g., three, four, five, or more) therapeutic compounds. In such formulations, each therapeutic compound may have a distinct target gene or there may be overlap in target genes and/or each therapeutic compound may have a target gene expressed in a distinct tissue type or there may be overlap in tissue types. Moreover, target gene may be expressed coincidentally in each tissue type or its expression may differ between tissue types. Again, as described above, for formulations containing more than two therapeutic compounds, consideration of the compounds' half-live and/or the lengths of the target genes' expression periods can be made when designing such formulation(s).
Example 6: Methods for Designing a Formulation to Induce Dipping in Non-Dippers Containing an Angiotensin Receptor Blocker (ARB) Plus a Beta Blocker or an Acetylcholinesterase (ACE) Inhibitor Plus a Beta Blocker “Dipping” is defined as a 10% or more drop in nighttime blood pressure relative to daytime blood pressure. A night time dip in blood pressure is normal and desirable, and the absence of a night time dip is associated with poorer health outcomes, including increased mortality. Additionally, nocturnal hypertension is associated with end organ damage.
Worldwide, there are 300-400 million non-dippers, roughly 10% of which live in the U.S., Europe, and Japan, and these non-dippers would benefit from a treatment that induces a dip in blood pressure.
Taking an angiotensin receptor blocker (ARB) or an acetylcholinesterase (ACE) inhibitor before bedtime is known to cause a drop in blood pressure. In a trial of bedtime administered Valsartan (an ARB), a 10 mmHg better result (bedtime, −21/−14, awakening, −13/−8, net 8 mmHg/6 mmHg) than the awakening group was observed. However, these results are less than the 10% drop in blood pressure required to be considered a dip. Thus, current treatment methods are insufficient to induce a dip in non-dippers.
To address this insufficiency, a formulation is designed that combines an ARB (e.g., Valsartan and Losartan) and a beta blocker (e.g., Metoprolol and Timolol) or an ACE inhibitor (e.g., Enalapril and Ramipril) with a beta blocker (e.g., Metoprolol and Timolol) to improve blood pressure dip in non-dippers.
As shown in Table 1, the target gene for Valsartan and Losartan is Agtr1a (also known as AGTR1) and as shown in Table 2, peak expression of Agtr1a in heart and kidney tissue type (tissues relevant to blood pressure dipping) occurs at circadian time 6 and its period extends for 12 hours. The minimum reported half-lives of Valsartan and Losartan are each one hour (see Table 1). Therefore, to effectively target peak expression of Agtr1a in heart and kidney, the formulation should be designed to initially release Valsartan or Losartan 2 hours after an at-bedtime administration and release should continue for 12 hours.
As shown in Table 1, the target gene for Enalapril and Ramipril is Ace, and as shown in Table 2, peak expression of Ace in lung and heart tissue types (tissues relevant to blood pressure dipping) occurs at circadian time 12 and its period extends for 12 hours. The minimum reported half-lives of Enalapril and Ramipril are each 2 hours (see Table 1). Therefore, to effectively target peak expression of Ace in heart and lung, the formulation should be designed to initially release Enalapril and Ramipril 8 hours after an at-bedtime administration and release should continue for 12 hours.
Additionally, as shown in Table 1, the target genes for Metoprolol or Timolol is Adrb1 and Adrb2, and as shown in Table 2, peak expression of Adrb1 in the lung tissue type (tissue relevant to blood pressure dipping) occurs at circadian time 6 and its period extends for 12 hours while peak expression of Adrb2 in lung and skeletal muscle tissue types (tissues relevant to blood pressure dipping) occurs at circadian time 12 and its period extends for 12 hours. The minimum reported half-life of Metoprolol is three hours (see Table 1). Therefore, to effectively target peak expression of Adrb1 and Adrb2 in the lung and skeletal muscle, the formulation should be designed to initially release Metoprolol 2 hours after an at-bedtime administration and release should continue for 12 hours.
Specific features of suitable formulations which allow extended-release or delayed-release of Valsartan/Losartan and Metoprolol or Enalapril and Ramipril and Metoprolol are known or can readily be ascertained by a skilled artisan in the field of pharmacology and can be found in a tome relevant to this field, see, e.g., “Remington: The Science and Practice of Pharmacy” 22nd edition, Allen, Loyd V., Jr. editor, Pharmaceutical Press, Hampshire, UK (2012).
Example 7: Methods for Designing a Formulation Containing and Angiotensin Receptor Blocker Plus an Extended-Release or Delayed-Release Diuretic Hypertension is often treated using therapies that include more than one active agent. For example, a commonly-used hypertension therapeutic is Diovan HCT® (Novartis, Basel, CH), which is a combination of an ARB (Valsartan) and a diuretic (hydrocholorthiazide, “HCT”). However, treatment with Diovan HCT® is problematic. While there is evidence that ARBs work better at night, the side effects of a diuretic, i.e., frequent urination, make a night-time release of the diuretic from Diovan HCT® undesirable. Instead, it would be better for the ARB to work at night and the diuretic work during the day. Thus, there is a need for a single-dose formulation that includes night-time release of an ARB and a daytime release of a diuretic.
To address this need, a suitable formulation is designed that combines an ARB (e.g., Valsartan and Losartan) and a diuretic (e.g., hydrocholorthiazide) to provide night-time release of the ARB and daytime release of the diuretic.
As shown in Table 1, the target gene for Valsartan and Losartan is Agtr1a (also known as AGTR1) and as shown in Table 2, peak expression of Agtr1a in heart and lung tissue type occurs at circadian time 6 and its period extends for 12 hours. The minimum reported half-lives of Valsartan and Losartan are each one hour (see Table 1). Therefore, to effectively target peak expression of Agtr1a in heart and lung, the formulation should be designed to initially release Valsartan or Losartan 2 hours after an at-bedtime administration and release should continue for 12 hours.
Likewise, as shown in Table 1, the target genes for hydrocholorthiazide are Car4, Cart, Car12, Car9 (also known as Ca4, Cat, Ca12, and Ca 9, respectively), and Slc12a2 and their peak expressions are at circadian times 6 to 12. Because hydrocholorthiazide is a diuretic, it is preferable to have it active when a subject is awake, when frequent urination is less troublesome. Therefore, the formulation is designed such that the hydrocholorthiazide is released independent of its target genes peak expressions. Specifically, the formulation is designed to initially release hydrocholorthiazide six to eight hours following an at-bedtime administration. Hydrocholorthiazide has a half-life of 5.6 hours (see Table 1). Therefore, the formulation can immediately release its hydrocholorthiazide or its release can continue for 12 hours using extended-release formulations, delayed-release formulations, or combination thereof.
Specific features of formulations which allow extended-release or delayed-release of Valsartan/Losartan and hydrocholorthiazide are known or can readily be ascertained by a skilled artisan in the field of pharmacology.
Example 8: Methods for Designing a Formulation Containing an Extended-Release or Delayed-Release Fibrate Fibrates are a class of drugs used to treat hyperlipidemia and hypertriglyceridemia. They act by activation of PPARs, principally the target gene PPARα in the liver. Fibrates are typically taken multiple times per day, usually with meals. For example, Bezafibrate is taken three times per day at 200 mg and Gemfibrozil is taken twice per day at 600 mg.
However, as shown in Table 2, PPARα exhibits a pronounced circadian rhythm, which peaks in the middle of the night. Additionally, lipoprotein lipase, a target of fibrates, also exhibits a nighttime cycling of activity. Because the target genes of fibrates have peak expression at night, it may be unnecessary to administer it during the day. Thus, a single-dose formulation which directs release of a fibrate during peak expression of PPARα is desirable.
As shown in Table 2, peak expression of PPARα in the liver occurs at circadian time 8 and its period extends for 8 hours, and as shown in Table 1, the minimum reported half-lives of Bezafibrate and Gemfibrozil are one hour and one and a half hours, respectively. Therefore, in order to effectively target peak expression of PPARα in liver, the formulation should be designed to initially release Bezafibrate or Gemfibrozil 4 hours after an at-bedtime administration and release should continue for 8 hours.
Specific features of formulations which would allow extended-release or delayed-release of Bezafibrate or Gemfibrozil are known or can readily be ascertained by a skilled artisan in the field of pharmacology.
Example 9: Methods for Designing a Formulation Containing a Short Acting Fibrate and a Short Acting Statin Fibrates and statins are often taken together to treat dyslipidemia. There is clinical evidence that short acting statins work better when taken at night, and, as described in Example 5, supra, fibrates may also work better at night. Despite this, current recommendations suggest that the two classes of medicines be taken separately, with fibrates taken in the morning and statins taken at night, possibly because certain commonly-prescribed fibrates (e.g., Gemfibrozil) and statins (e.g., Simvastatin) are metabolized by the same enzymes, Cyp3a4. Consequently, when taking a fibrates in combination with a statin, levels of statins can remain high, and myopathies and rhabdomyolysis (breakdown of muscle fibers) can occur more frequently. Thus, a single-dose formulation that overcomes this drug interaction is warranted. For example, a formulation containing a short acting fibrate (i.e., Gemfibrozil), whose target gene's expression peaks approximately four hours earlier at night than the target gene of a short acting hydrophilic statin (i.e., Fluvastatin).
Peak expression of Gemfibrozil's target gene, PPARα, occurs at circadian time 8 in the liver with its expression extending for 8 hours, and Gemfibrozil's half-life is one and a half hours. Therefore, to effectively target peak expression of PPARα in liver, a suitable formulation to treat dyslipidemia should be designed to initially release Gemfibrozil 2 hours after an at-bedtime administration and release should continue for 6 hours.
As shown in Table 1, the target gene for Fluvastatin in the liver is Hmgcr. Peak expression of Hmgcr occurs four hours following peak expression of PPARα. As shown in Table 2, Hmgcr expression period extends for 12 hours. Likewise, as shown in Table 1, the half-life of Fluvastatin is three hours. Therefore, to effectively target peak expression of Hmgcr in liver and avoid interactions Gemfibrozil, the formulation should be designed to initially release Fluvastatin 6 hours after an at-bedtime administration and release should continue for 12 hours.
Specific features of formulations which allow extended-release or delayed-release of Gemfibrozil and Fluvastatin are known or can readily be ascertained by a skilled artisan in the field of pharmacology.
Example 10: Methods for Designing a Formulation Containing Delayed-Release, Immediately-Released Niacin Niacin and extended-release formulations of niacin, e.g., Niaspan, are often taken to treat dyslipidemia. Niacin is typically given at high dosage, 500 mg (normal dietary intake is 15 mg for adults), to achieve its lipid lower effects. At these concentrations, flushing and liver function abnormalities can occur. In a Niaspan trial, half of patients taking 1000 mg dosage withdrew before the study was completed.
However, as shown in Table 2, Niacr1, a receptor for niacin as shown in Table 1, exhibit a pronounced circadian rhythm, which peaks after bedtime. Because the target genes of niacin have peak expression at night, it may be unnecessary to administer it during the day and thereby avoid niacin's side effects (e.g., flushing) during waking hours. Thus, a single-dose formulation which directs release of niacin after bedtime and/or at peak expression of Niacr1 is desirable; in particular, a delayed release, rather than extended-release, formulation of niacin, which could be taken at a reduced dosage (<500 mg).
As shown in Table 2, peak expression of Niacr1 in the adrenal tissues occurs at circadian time 4 and its period extends for 8 hours. Therefore, in order to effectively target peak expression of Niacr1 in the adrenal, the formulation should be designed to initially release niacin about 4 hours after an at-bedtime administration and immediate-released at that time.
Specific features of formulations that would allow delayed-release of niacin are known or can readily be ascertained by a skilled artisan in the field of pharmacology.
Example 11: Methods for Designing a Formulation Containing Immediately-Released Niacin and a Short Acting Statin Niacin and extended-release niacin formulations are often taken with a statin to treat dyslipidemia. As noted in Example 7, the high doses required to achieve niacin's lipid lower effects cause unwanted side effects. Also, as mentioned above, Niacr1 (also known as HCAR2) exhibit a pronounced circadian rhythm, which peaks after bedtime. Because the target genes of niacin have peak expression at night, administer niacin at bedtime could avoid niacin's side effects (e.g., flushing) during waking hours. As shown in Table 1, the half-life of niacin is 0.33 hours.
As shown in Table 1, the target gene for Cerivastatin, Fluvastatin and Simvastatin (three statins with half-lives of less than three hours) in the liver is Hmgcr. Peak expression of Hmgcr occurs in the liver at circadian time 12. Thus, administering a statin at bedtime and releasing the statin thereafter will allow the statin to act when its target's expression has peaked. Moreover, peak expression of Niacr1 occurs in the adrenal tissue at circadian time 4, which is 8 hours before peak expression of Hmgcr.
Therefore, to effectively target peak expression of Hmgcr in liver and avoid interactions niacin, a formulation should be designed to initially release niacin about 2 hours after an at-bedtime administration and the statin should be released 6 hours after administration.
Specific features of formulations which would allow delayed-release of niacin and/or a statin are known or can readily be ascertained by a skilled artisan in the field of pharmacology.
The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.